Johan Smitz1
(1)
Laboratory for Endocrinology and Tumor Markers/Follicle Biology Laboratory, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, Brussels, 1090, Belgium
Johan Smitz
Email: johan.smitz@uzbrussel.be
Abstract
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) have been used in diagnostics and therapeutics from biologically purified sources. Though both hormones function via the same receptor (LHCGR), mostly hCG has been used due to its widespread availability. Hence, in the mind of the practising physician, both molecules have been considered equal. The recent availability of recombinant LH has led us to reconsider the specificities of both hormones in terms of actions on the body.
LH and hCG play essential roles in the reproductive cycle. LH plays a key role in follicular maturation and the ovulation process, and hCG is the “pregnancy hormone.”
LH and hCG are different in terms of structure, expression, regulation, and function. LH and hCG fundamentally differ in their expression patterns and have complex and unique aspects. LH and hCG should be considered as hormone mixtures, the composition of which fluctuates during the course of the ovarian cycle and pregnancy and throughout the lifespan of men and women. Diverse isoforms have distinct functions, reflected by their relative abundance in normal and aberrant physiologic processes. Quantitative and qualitative distinctions in signaling cascades, activated by LH and hCG have been recently discovered; furthermore, the extragonadal activities are currently under exploration. Availability of recombinant LH and hCG as new therapeutic tools for use in specific clinical pro-fertility conditions could lead us to reconsider the specific indications for each of both molecular entities. The first part of this chapter reviews the current knowledge on both parent molecules, emphasizing their specificities and the consequences at the receptor level.
Keywords
GonadotropinLuteinizing hormone/choriogonadotropin receptorLuteinizing hormone receptorHuman chorionic gonadotropinOvarian stimulationIn vitro fertilization
Introduction
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) have been used in diagnostics and therapeutics from biologically purified sources. Though both hormones function via the same receptor (LHCGR), mostly hCG has been used, due to its widespread availability. Hence, in the mind of the practising physician, both molecules have been considered equal. The recent availability of recombinant LH has led us to reconsider the specificities of both hormones in terms of their actions on the body.
LH and hCG play essential roles in the reproductive cycle. LH plays a key role in follicular maturation and ovulation process, and hCG is the “pregnancy hormone” [1].
LH and hCG are different in terms of structure, expression, regulation, and function. LH and hCG fundamentally differ in their expression patterns and have complex and unique aspects. LH and hCG should be considered as hormone mixtures, the composition of which fluctuate during the course of the ovarian cycle and pregnancy and throughout the lifespan of men and women. Diverse isoforms have distinct functions, reflected by their relative abundance in normal and aberrant physiologic processes. Quantitative and qualitative distinctions in signaling cascades, activated by LH and hCG have been recently discovered; furthermore, the extragonadal activities are currently under exploration. Availability of recombinant LH and hCG as new therapeutic tools for use in specific clinical pro-fertility conditions could lead us to reconsider the specific indications for each of the molecular entities. The first part of this chapter reviews the current knowledge on both parent molecules, emphasizing their specificity and the consequences at the receptor level.
Molecular Structure
Luteinizing hormone and hCG are heterodimeric glycoproteins, comprised of α and β subunits. hCG retains the full 145 − amino acid complement in its β-subunit. As for LH, the β-subunit undergoes cleavage of its 24-amino acid leader sequence to generate its final 121-amino acid sequence.
Due to structural differences and post-translational modifications, hCG is more stable and has a longer circulating half-life than LH. Due to the heterogeneity of circulating isoforms, the half-lives of these molecules should be expressed as a range: minutes for LH and hours for hCG. The shorter half-life of LH is physiologically relevant, as it allows production of LH pulses. The longer half-life of placental hCG and its greater receptor binding affinity make it more bioactive than hLH [2, 3].
Molecular Forms in the Circulation
Luteinizing Hormone
Gonadotropic cells of the adenohypophysis produce LH, which regulates ovulation. In a normal menstrual cycle, a surge in LH induces ovulation from the dominant follicle. In the first part of the follicular phase, LH stimulates androgen production in thecal cells. These androgens are aromatized by the granulosa cells to estrogen under influence of FSH. Prolonged, exponentially increasing estrogen levels induce a positive feedback on the pituitary gland and the subsequent LH surge results in ovulation [4]. LH promotes progesterone production, supporting development of the corpus luteum [5]. Variations in LH isoform composition are observed during the reproductive life cycle. In general, LH isoforms with shorter half-lives but increased biopotency are present in younger postpubertal women, whereas longer-lived LH isoforms prevail in postmenopausal women [6, 7]. Women with polycystic ovarian syndrome (PCOS)—an endocrine condition associated with altered folliculogenesis and anovulation—appear to predominantly secrete LH isoforms that have a high ratio of biological-to-immunological activity [8, 9].
Human Chorionic Gonadotropin
Four physiologically important isoforms of hCG have been described: regular hCG, hyperglycosylated hCG (h-hCG), hyperglycosylated free hCG β subunit, and pituitary hCG. Different cell types produce these isoforms, which display disparate half-lives and biologic functions. Isoforms have unique, although sometimes overlapping, functions: the four variants share a common protein sequence (β subunit), but each is modified differently.
After an initial early surge of h-hCG regular hCG is secreted by differentiated syncytiotrophoblasts. It is the prevailing hCG species measured in serum during pregnancy [10]. Historically, it was believed that hCG induced promotion of progesterone secretion by the corpus luteum in early pregnancy. However, hCG has other functions during pregnancy as its levels continue to increase after hCG is no longer needed for progesterone production [11].
Human chorionic gonadotropin is additionally involved in placentation: maintaining angiogenesis of the uterine vasculature and promoting differentiation of cytotrophoblasts into syncytiotrophoblasts [12–14]. Proposed roles for regular hCG comprise fostering implantation, preventing fetal rejection, co-ordinating uterine and fetal growth, and, potentially, growth and development of fetal organs [10].
During the implantation process, extravillous cytotrophoblasts and h-hCG concentrations peak early in the first trimester [10]. The structural difference between regular hCG and h-hCG is the complexity of the oligosaccharide side chains; h-hCG tends toward oligosaccharides with a greater number of sugar residues. The percentage of hCG in the form of h-hCG subsequently declines, becoming a minor component of total hCG measurement during the last two trimesters.
The association between pregnancy loss and low h-hCG levels supports a key role for this variant in implantation [15, 16].
Pituitary hCG is secreted by gonadotropic cells of the anterior pituitary. Pituitary hCG has a shorter half-life than its placental counterpart due to the higher number of sulfonated side chains [17]. The concomitant temporal appearance of hCG with LH during the menstrual cycle and their common receptor suggest that it functionally may mimic LH and support the progesterone production during the luteal phase [10].
Metabolism
One of the initial steps in hCG degradation is proteolytic cleavage of the β subunit (possibly by human leukocyte elastase), which generates a “nicked” form of the protein. Nicked hCG rapidly dissociates into its component α and β subunits. h-hCG dissociates more readily than regular hCG. The nicked β subunit is further degraded, predominantly in the kidneys, resulting in a predominant β-core fragment in urine [11, 18, 19].
The extent of gonadotropin glycosylation dictates molecular charge determining clearance rate. The more acidic isoforms have a longer half-life in vivo [20]. The grade of sialylation of LH positively correlates with the metabolic clearance rate [21].
The Common Luteinizing Hormone/Choriogonadotropin Receptor, Its Polymorphisms and Mutations
Luteinizing Hormone and hCG bind to and activate a common receptor, the LH/choriogonadotropin receptor (LHCGR), also known as the LH receptor (LHR) [22, 23]. LHCGR is expressed by multiple cell types in the ovary: thecal, luteal, interstitial, and differentiated granulosa cells. Expression of LHCGR in these cell types during the ovarian cycle is dynamic, depending on changes in the hormonal milieu [24]. LHCGR is downregulated transiently after the preovulatory LH surge, reaches a maximum at the mid-luteal phase, and decreases with corpus luteum regression. This pattern is the inverse of what has been observed for bioactive LH isoforms, where biologic-to-immunologic activity is maximal at mid-cycle and reaches a nadir during the luteal phase [25]. Temporal changes in LHCGR expression involve transcriptional as well as post-transcriptional regulation [24].
Mutations in LHCGR are associated with developmental and reproductive abnormalities, including psuedohermaphrodism, micropenis, hypospadias, and infertility [22, 24]. More recent suggestions state that polymorphisms in the LHCGR sequence contribute to risk for conditions associated with infertility, including PCOS. A genome-wide association study detected a link between a polymorphic marker in the region of LHCGR and PCOS in Han Chinese women (confirmed in a subsequent case-control cohort) [26]. Interestingly, the specific polymorphic marker, associated with PCOS in the Han population, failed to correlate with PCOS in Caucasian [27, 28].
Signaling Pathways Linked to LHCGR
LHCGR is capable of binding αβ dimeric LH, hCG, and h-hCG. Also, nicked hCG binds LHCGR, but with a much lower affinity [29, 10, 11]. LHCGR signaling pathways are a subject of active investigation: it is generally accepted that the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway drives the downstream events inducing ovulation and the steroid biosynthesis processes.
Many other signaling pathways are however, triggered: LHCGR stimulation also activates the phospholipase C/inositol phosphate (PLC/IP) signaling pathway [30], but it has been suggested that PLC-based signaling only occurs during the preovulatory LH surge and during pregnancy when levels of its ligands are high. Investigators have recently reported PLC to be the mediator of final granulosa cell differentiation in response to LH [31].
In addition, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and AKT have been identified as major downstream players in LHCGR-mediated signaling [32, 33]. The ERK1/2 and AKT pathways participate in the regulation of oocyte and follicle maturation [34, 35].
As LH and hCG were considered to be functionally equivalent, the post receptor effects were traditionally presumed to be similar. New data, however, suggests that this is not true. In recent experiments, phospho-ERK1/2 levels were reported to be greater in cultured human granulosa cells after long-term exposure to LH compared with hCG [36].
The Evidence for Extragonadal LHCGR
Detection of LHCGR in regions other than ovarian cell types, including the decidua, uterine vasculature, umbilical cord, fetal organs, cytotrophoblast cells, and adrenal cortex, has fueled a debate regarding the potential role for gonadotropins in extragonadal locations [10, 37, 38].
Emerging new data propose that extragonadal LHCGR has functional significance; further study is needed to clarify its role in normal and aberrant cellular processes and to characterize the individual effects of various LH and hCG isoforms.
Physiology
By understanding how LH and hCG affect normal and abnormal human development and reproduction, current treatments for reproductive disorders may be improved while uncovering other medical disciplines where diagnostic and therapeutic measures of these gonadotropins may be of use, e.g., in cancer. The physiology of LH and hCG throughout the reproductive lifespan and the impact of disrupting their normal expression profiles and functionality are concisely summarized as follows.
The Basal LH Secretion Pattern
The increase in gonadotropin activity during puberty drives gonadal steroidogenesis—primarily testosterone and progesterone by thecal cells in females [39]. Most aromatizable androgens, generated by thecal cells, are converted to estradiol by the granulosa cells. Testosterone, estradiol, and adrenal androgens produce the physical changes associated with puberty. As estradiol production increases, stimulation of the endometrium occurs, eventually leading to menarche (approximately 2–3 years after the first signs of puberty). The reproductive axis matures in middle-to-late puberty, with the establishment of estrogen positive feedback leading to the LH surge [40]. Ovulatory cycles do not become established until some years after menarche.
After puberty, the pattern of LH secretion during the menstrual cycle becomes more regular in normo-ovulatory women. In most women with PCOS, however, higher basal levels of LH are the result of increased pulse frequency and amplitude throughout the cycle [41–43]. This lack of variation in LH secretion pattern contributes to the anovulatory cycles, often found in women with PCOS.
The Roles of LH and hCG During Ovulation and Pregnancy
In the first part of the follicular phase, estradiol exerts a negative feedback effect on LH; however, LH activity stimulates thecal cell production of androgens for estradiol production by the granulosa cells. As estradiol levels rise exponentially in the second part of the follicular phase, a positive feedback effect is induced, leading to the LH surge and subsequent ovulation [44]. With ovulation, the ovulatory oocyte reinitiates meiosis I and progresses through to meiosis II. LH drives progesterone production and secretion from the corpus luteum until, if pregnancy occurs, hCG will induce its survival. Initially hCG is mostly the hyperglycosylated isoform (h-hCG) [45].
What is less well known is that low levels of pituitary hCG parallel the dynamics of LH secretion during the menstrual cycle [46]. The role of this pituitary hCG is unclear, but the pattern of expression suggests an overlapping one to that of LH [10]. A suggestion is that hCG expression may elevate the peak range of LH, thereby aiding in the promotion of ovulation and the early secretion of progesterone [11].
Roles of LH and hCG on Fertilization and Implantation
The presence of LHCGR in human Fallopian tubes and sperm suggests a role for LH and hCG in fertilization [47, 48]. Expression of LHCGR is greater in Fallopian tubes during the luteal phase compared with the proliferative phase of the menstrual cycle or Fallopian tubes from postpartum or postmenopausal women [47].
Secretion of hCG by the blastocyst may elicit a cross talk with endometrium to allow implantation [49, 50]. Endometrial LHCGR expression increases in mid-luteal phase at a time where the endometrium is receptive to implantation (i.e., the implantation window) [50]. Some researchers claim that a blastocyst, producing locally high levels of hCG could extend the implantation window [49].
Human choronic gonadotropin is also believed to support implantation and placentation by remodeling endometrial tissue, promoting maternal immunotolerance of fetal tissue, inducing neoangiogenesis, and increasing the natural killer (NK) lymphocyte population [10, 49, 50]. As the effects of fostering endometrial receptivity were initiated even before embryonic hCG expression, researchers found epithelial hCG is expressed and produced in the human endometrium biopsy specimens during the early to mid-secretory phase of the menstrual cycle [51]. Further studies on the role of hCG on endometrium, related to implantation, should be conducted.
Pathology of LH, hCG, and LHCGR
Mutations at the level of LH, hCG, and their common receptor (LHCGR) have taught us the extent to which LH and hCG signaling is required for the formation and development of the reproductive organs throughout life and its importance in fertility regulation. Observed gene alterations may be naturally occurring, as is the case for human mutations/polymorphisms, or induced in mouse knock-out models. A description of human phenotypes associated with changes in LH, hCG, and LHCGR function or expression are summarized in Table 3.1.
Table 3.1
Phenotypes associated with mutations in human LHβ, CGB, and LHCGR genes
|
Gene and type of mutation |
Phenotype |
Effect on fertility |
|
LHβ |
||
|
Inactivating |
Oligomenorrhea, secondary amenorrhea |
Infertile |
|
Polymorphisms |
Endometriosis, hyperprolactinemia, luteal insufficiency, menstrual disorders, PCOS |
Reduced fertility |
|
CGB |
||
|
Polymorphism |
Recurrent miscarriage |
Reduced fertility |
|
LHCGR |
||
|
Activating |
Leydig cell adenoma |
Reduced fertility |
|
Inactivating |
Oligomenorrhea/amenorrhea, empty follicle syndrome |
Infertile |
LHβ luteinizing hormone β-polypeptide, CGB chorionic gonadotropin β-polypeptide, LHCGR luteinizing hormone/choriogonadotropin receptor, PCOS polycystic ovary syndrome
Human Mutations/Variants
LHβ
Naturally occurring mutations, resulting in inactive LH, are rare in women. Two cases in female patients with inactivating LHβ mutations have been described [52, 53]. Characterization of one of these individuals revealed normal development and appropriate pubertal milestones followed by secondary amenorrhea and infertility [52]. The reproductive findings in these women confirm that adequate LH is not absolutely needed for normal sexual differentiation and puberty, but essential for ovulation and corpus luteum functionality.
hCG
It has been hypothesized that mutations with a significant effect on hCG would not be compatible with successful pregnancy and are thus not found [54]. It seems logical that polymorphisms in the hCG β-subunit (i.e., the CGB gene) are associated with an increased risk of recurrent miscarriage [54].
LHCGR
Activating and inactivating mutations have been described in the LHCGR gene. Women with activating LHCGR mutations display no functional reproductive abnormalities. On the other hand, patients with inactivating mutations of LHCGR have a similar phenotype to that of inactivating LHβ mutations, including oligomenorrhea and infertility [55]. An LHCGR mutation that is believed to reduce receptor expression and binding capacity has been implicated in empty follicle syndrome [56]. In general, the loss of function of LHCGR mutations had only generated overt reproductive pathology in the homozygous state (i.e., autosomal recessive inheritance).
Pharmacological Uses of LH and hCG
Actions of LH Bioactivity on Follicle and the Relation with Oocyte Quality
In humans, physiological follicular growth is driven by a delicate interplay between FSH and LH that affects theca and granulosa cells, leading to the selection of a single dominant follicle through a series of feedback mechanisms [57]. Effects of LH are mediated via LH receptors, which are expressed as soon as theca cells are present on secondary follicles. Theca cells play a unique role in the generation of androgens and growth factors, which influence growth and differentiation of granulosa cells that are under endocrine control of FSH via the presence of FSH receptors. FSH drives the development of the granulosa cell compartment and is essential for follicle survival and differentiation. Effects of FSH are amplified via several paracrine loops, including the products of aromatization that depend upon the provision of androgens by the theca cells. Multiple follicular recruitment can be obtained by applying supraphysiological amounts of FSH alone [58, 59]. While supraphysiological amounts of FSH can increase survival of many follicles in one cycle and provide an increased oocyte production, serum LH concentrations seem to determine a favorable outcome only when kept within certain limits. The exact amounts of administration of LH and/or hCG to administer in combination with FSH to obtain successful pregnancies have been under recent scrutiny [60–63]. With the progression of follicle growth, LH receptors are expressed on the granulosa cells. It has been shown that in human, follicles of 10 mm diameter are becoming responsive to LH action [64, 65]. Receptors for LH are highest in the mural granulosa cells closest to the basement membrane and their density decreases centripetally. Demonstration of expression of LH mRNA and receptor protein in cumulus-corona might be species specific and is influenced by differences in assay specificity, type of follicles from which the cumulus-oocyte complexes (COC) are isolated, the hormonal supplements used in the incubation medium and timing of the analysis after isolation and culture of the cumulus cells [66–68]. LH action on the oocyte itself is indirect: there is an upregulation of EGF-like substances in the mural granulosa cells that have their receptors in the cumulus cells [69, 70]. LH activity in the follicular environment positively influenced early embryonic development in primate, bovine, and ovine [71–73] and has also previously been associated with conception cycles in patients undergoing COH for ART [74–76].
Ovulation Induction and Ovarian Stimulation: A Modulatory Role by LH Bioactivity
In a minority of female patients consulting for anovulation, the origin of the defect is in the central nervous system at the hypothalamic or pituitary level (anovulation WHO type I). These women have no measurable FSH and LH. Restoration of a cycle can either be obtained by pulsatile lueinizing hormone-releasing hormone (LHRH) treatment or by gonadotropin administration. In this case, a direct gonadotropin substitution is preferred and there is an absolute need to administer LH bioactivity. As human menopausal gonadotropins (hMGs) contain equipotent LH and FSH amounts, there is a constant LH supply always available in ovulation induction (OI) schemes. In the case that treatment with recombinant follicle-stimulating hormone (r-FSH) is considered, there is a need to co-administer recombinant LH (r-LH) or recombinant hCG (r-hCG).
For all other indications for ovulation induction therapy (WHO type II or type III), there is sufficient endogenous LH background concentration present to allow follicle growth and endometrial preparation. In principle, OI could be performed with r-FSH only, however, in patients with polycystic ovary disease, there are now good indications that highly purified hMG (HP-hMG) is equally effective and has a reduced number of complications, such as multiple pregnancy and early onset hyperstimulation syndrome, which is accompanied with a lot of discomfort for the patients [77]. According to the ceiling theory, the LH level present in the daily injections may prohibit the transition of small to medium-sized follicles in the cohort to grow further up to the preovulatory stage [57]. Hence, it was proposed to consider a biphasic type of treatment for ovulation induction, wherein phase 1 FSH is used, followed with LH (or hCG) when the largest follicle has reached 13–14 mm (a stage at which it has acquired the LH receptor). The administration of LH would then take over the function of FSH in those follicles expressing LH receptors. In the smaller follicles, where LH receptor on granulosa is still insufficiently expressed, the LH support would not be functional, leading the follicles into atresia.
In summary, regarding the role of LH, its dose and time of administration at a particular stage of follicular growth are very important; its presence is essential to drive known theca cell functions such as steroidogenesis and provision of paracrine factors to granulosa. However, LH is a double-edged sword: an excess of LH would drive the small follicles into atresia due to accumulated androgens which remain unconverted (in small follicles aromatase is still inactive). Depending on whether mono- or multiple folliculogenesis is desired, timely administration of LH in combination with FSH is important to modulate the ovarian response.
Use of LH or hCG in Ovarian Stimulation for ART
Conditions in Need of LH or hCG Supplementation
In circumstances, where patients had a profound desensitization prior to stimulation (e.g., in the “long” GnRH protocol), an iatrogenic state of shortage of LH activity can be induced. When the gonadotropin preparation used for stimulation does not contain LH activity, an LH shortage might result in these women [78, 79]. The degree of gonadotropin suppression is dependent on the type of GnRH analog used and on their route and frequency of administration [80–82]. Regarding the serum LH concentrations measured after gonadotropin treatment, there was significantly more circulating LH present in patients treated with an hMG preparation than those exposed to r-FSH alone [79]. FSH stimulation of the gonads provokes signals back to the hypothalamic-pituitary axis via ovarian steroids and gonadal peptides that suppress the endogenous gonadotropin secretion [83]. A retrospective analysis of serum hormone profiles in 71 patients downregulated with a GnRH agonist (Decapeptyl) revealed a surprisingly high incidence of 50 % of the patients with low LH (≤1 IU/L) when treated with r-FSH after pituitary desensitization. Compared to the HP-hMG patients, estradiol concentrations produced by granulosa cells from the r-FSH only treated group were significantly lower. The difference in estradiol (E2) output can be explained by the responsiveness of theca cells to the constant exposure to hCG in the HP-hMG group. Increased E2 levels in HP-hMG are the reflection of an increased production of E2 per follicle through a higher provision of androgen precursor molecules. Serum androstenedione and total testosterone concentrations are significantly elevated throughout the last days of stimulation in HP-hMG cycles. The occurrence of pregnancy in relation to steroid exposure levels over the last 8 days of stimulation treatment was inversely correlated with progesterone (≤0.71 μg/L), androstenedione (≤2036 ng/L), and the free androgen index (FAI) (≤0.013) in HP-hMG treatments. Values over the median value for these two parameters for the entire population reduced the occurrence of a pregnancy by a factor 2 to 3, emphasizing the existence of an endocrine profile which when exceeded was associated with a negative outcome. Similar relationships between steroid levels in circulation during the preovulatory period and the prevalence of conception by IVF treatment have been previously documented [84].
Ceiling Doses for HCG and LH
Using the current HP-hMG preparations throughout the entire stimulation phase in GnRH agonist downregulated patients does not induce premature luteinization of the large follicles as long as the daily administration dose remains under 100 IU, which is a dose well above the hCG provision, which would be administered by regular treatment [63]. It is expected that daily administration of equivalent doses of recombinant LH from the beginning of the stimulation is also safe [85]. Also, another team, who studied GnRH agonist-suppressed infertile women treated with different FSH preparations, demonstrated no correlation between rising preovulatory progesterone concentrations and LH activity [86, 87], but rather, a strong positive correlation with serum FSH. Moderate progesterone increments have been observed in severely downregulated patients treated exclusively with recombinant FSH [88, 89]. Supraphysiological doses of FSH are able to induce progesterone elevations and to increase thecal androgen production. Supraphysiological FSH levels mobilize factors from granulosa cells that promote the production of progesterone by the theca cells [90].
Routine LH or hCG Bioactivity in Combination to FSH
Large clinical trials, comparing the use of HP-hMG with r-FSH in GnRH agonist downregulated and in GnRH antagonist suppressed patients (700 and more patients per study) demonstrated higher live birth rates in the hCG containing HP-hMG preparation. The mechanisms behind the positive effects of low hCG levels on gamete quality still remain largely enigmatic. The studies with HP-hMG suggest that constant background of LH bioactivity in the form of hCG during the preovulatory phase has a major impact upon the steroid environment with potential downstream effects on gamete competence. In large prospective randomized studies comparing the use of HP-hMG to r-FSH in combination with GnRH analog for IVF, HP-hMG yielded higher live birth rates, despite a lower oocyte recovery rate, compared to r-FSH. In the Merit® trial, part of the explanation for superior results with HP-hMG could be attributed to the higher embryo quality parameters and higher implantation rates in HP-hMG top-quality embryos [75]. The reason for better embryological outcomes in HP-hMG is not known; beneficial effects from a paracrine environment, induced by LH bioactivity on oocyte cytoplasmic maturation might involve androgen action, epidermal growth factor (EGF)-like factors, or factors from the transforming growth factor-beta (TGFβ) superfamily, linked to developmental competence [69, 70, 91]. Larger prospective studies are needed to evaluate the significance of LH exposure at the molecular level in oocytes and embryos and to clarify suggested differences in hCG or LH effects.
Conclusions
The availability of recombinant products with very specific and distinct bioactivity allows further study of the actions of LH and hCG. Clinical data suggest that the effects of the two molecular entities, working via the same hLHCG receptor might be different. Many reasons for the observed differences have already been provided, but the high molecular complexity of the two hormones and their interaction on the reproductive organs need further study.
Acknowledgments
The author thanks Dr. Lea Thuesen, Prof. A.N. Andersen, Dr. J.-C. Arce for fruitful discussions over the last years regarding the pharmacological use of hCG for ovarian stimulation.
Disclosure Statement
J.S. has nothing to disclose.
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