The role of LH in ovarian stimulation

Exogenous LH: let's design the future

Delphine P. Lévy1, José M. Navarro1, Glenn L. Schattman1,2, Owen K. Davis1 and Zev Rosenwaks1

1 The Center For Reproductive Medicine and Infertility, Weill Medical College of Cornell University, New York, USA


    Abstract
 Top
 Abstract
 Introduction
 LH physiology and actions
 Oestrogen actions
 Clinical implications
 Conclusions
 References
 
Historically, follicular stimulation protocols have included both FSH and LH in an attempt to mimic the physiology of normal human folliculogenesis. However, many recent gonadotrophin administration regimens have completely eliminated LH bioactivity. The importance and the amount of LH necessary for optimal follicular stimulation has been a topic of debate. Several recent studies have added to our understanding of the actions of androgens, oestrogens, gonadotrophins, and insulin on the follicle–oocyte unit, allowing a less speculative approach. Moreover, the availability of human gonadotrophins synthesized by recombinant DNA technology and gonadotrophin-releasing hormone (GnRH) antagonists, should soon permit a precise in-vivo assessment and re-evaluation of the historical 2-cell, two-gonadotrophin hypothesis. These pharmacological tools may also provide essential insights into the physiological roles of FSH and LH in human follicular development and oocyte maturation. The recombinant gonadotrophins give clinicians the unique opportunity to tailor ovarian stimulation regimens according to the patient's medical history, in an effort both to maximize oocyte yield and to improve oocyte quality.

Key words: folliculogenesis/IVF/LH/ovarian stimulation


    Introduction
 Top
 Abstract
 Introduction
 LH physiology and actions
 Oestrogen actions
 Clinical implications
 Conclusions
 References
 
The pharmacology of ovarian stimulation has been influenced by the 2-cell, two-gonadotrophin theory (Figure 1Go) (Fevold, 1941Go; Short, 1962Go) and, historically, follicular stimulation protocols have included both LH and FSH in an attempt to mimic the normal physiology of folliculogenesis. Differing views on the role of LH in ovarian stimulation, and the availability of recombinant human FSH (rhFSH), contribute to this divergence of treatment approaches for ovarian stimulation. Currently, many protocols for gonadotrophin administration have eliminated LH bioactivity. However, several recent primate studies have added to our understanding of the ovarian actions of androgens, oestrogens, and gonadotrophins, allowing a less speculative approach (Zelinski-Wooten et al., 1995Go; Vendola et al., 1998Go). Indeed, if androgens do not promote follicular atresia, if the presence of LH directly influences oocyte quality or embryo growth, and if excessive LH concentrations are detrimental only to polycystic ovary syndrome (PCOS) granulosa cells, then the addition of LH to ovarian stimulation protocols might have beneficial effects.



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Figure 1. The 2-cell, two-gonadotrophin theory. E2 = oestradiol

 
The recent availability of human LH and FSH synthesized by recombinant DNA technology, and the availability gonadotrophin-releasing hormone (GnRH) antagonists, should allow a precise in-vivo assessment and re-evaluation of the 2-cell, two-gonadotrophin hypothesis. These pharmacological tools may also permit new insights into the physiological roles of FSH and LH in follicular development and oocyte maturation. Finally, they give us the unique opportunity to tailor ovarian stimulation regimens according to the patient's medical history and previous response to treatment. Clinical studies comparing preparations containing LH activity with FSH-only regimens have focused on pregnancy outcome, number of oocytes retrieved and cancellation rates. However, in order to evaluate the importance of LH in ovarian stimulation, the end-points studied should probably also include oocyte quality, fertilization rates, embryo growth rates and quality, implantation rates, embryo cryosurvival, and possibly blastocyst formation. Whether the adjunct of LH is necessary, or at least beneficial, during ovarian stimulation has been an ongoing matter of debate (Filicori, 1999Go).


    LH physiology and actions
 Top
 Abstract
 Introduction
 LH physiology and actions
 Oestrogen actions
 Clinical implications
 Conclusions
 References
 
Steroidogenesis: what if androgens promoted follicular growth?
LH has essential and well-established roles in both ovarian steroid synthesis and ovulation. While normal ovulation is impossible without LH (Weiss et al., 1992Go; Latronico et al., 1996Go; Toledo et al., 1996Go), the specific role of LH in folliculogenesis and oocyte maturation is less clear. Thecal cells (TC) express LH receptors constitutionally, and LH stimulates androgen substrate production by the TC from fetal life until after the menopause (Adashi, 1996Go; Gougeon, 1996Go). Granulosa cells (GC) acquire their own LH receptors in the mid- to late follicular phase under the influence of FSH (Erickson et al., 1979Go). At that stage, FSH and LH act in synergy to support follicular development, increase GC aromatase activity and inhibin production, as well as prepare the follicle and its oocyte for the mid-cycle LH surge.

Androgens serve as substrate for GC oestrogen production through aromatization, but may also have an ovarian autocrine/paracrine role. Androgens were thought to be involved in follicular atresia and GC apoptosis because of their actions in the rodent ovary (Billig et al., 1993Go). However, recent evidence suggests that they may act as growth factors in primate preantral and small antral follicles (Vendola et al., 1998Go). Indeed, androgen receptor (AR) mRNA expression is most abundant in GC from healthy preantral and antral follicles in the primate ovary (Hillier et al., 1997Go; Weil et al., 1998Go), and is significantly increased in GC of testosterone-treated monkeys. More importantly, AR mRNA abundance is positively correlated with GC proliferation, and is negatively correlated with GC apoptosis (Weil et al., 1998Go). Locally-produced androgens are thought to enhance the FSH responsiveness of immature follicles, thereby promoting the selection of the follicles that will achieve full pre-ovulatory maturity under FSH stimulation (Hillier, 1999Go). Indeed, testosterone treatment significantly increases FSH receptor mRNA expression in GC obtained from rhesus monkey follicles at all stages (Weil et al., 1999Go). Taken together, these observations suggest that androgens, in addition to serving as precursors for GC oestrogen synthesis, also have a trophic role in primate follicular development. The same authors observed that FSH treatment markedly increased AR expression in primary follicles, providing a possible physiological mechanism whereby FSH promotes early follicular development (Weil et al., 1999Go). Thus, not only do androgens not induce the atresia of primate follicles, but they appear to act synergistically with FSH to promote follicular growth and steroidogenesis.

Absence of LH in humans: the experiments of nature
Several clinical situations, where LH is either absent or completely inactive, provide important clues to our understanding of the roles of LH in follicular development. In Kallmann's syndrome, women are profoundly hypogonadotrophic, and follicle development may be induced by the exogenous administration of gonadotrophins. Treatment of these patients with purified or recombinant FSH alone allows multiple follicle development, but produces inadequate oestradiol concentrations. In some studies, fewer pre-ovulatory follicles developed compared with patients treated with combination of FSH and LH (Shoham et al., 1991Go), while others have observed no differences (Balasch et al., 1995Go). Administration of FSH without LH to hypogonatrophic hypogonadal patients results in lower serum and follicular fluid oestradiol concentrations, normal inhibin concentrations, decreased endometrial thickness, reduced occurrence of ovulation, reduced oocyte fertilization rates, and lower embryo cryosurvival rates, when compared with HMG treatment (Shoham et al., 1991Go; Schoot et al., 1994Go; Balasch et al., 1995Go; Kousta et al., 1996Go). More importantly, no pregnancies were observed in these women when they received FSH alone for ovarian stimulation, despite oestradiol replacement (Hull et al., 1994Go; Balasch et al., 1995Go). The heterogeneity of the hypogonadotrophic hypogonadism syndromes, and the possible persistence of endogenous LH secretion, may explain some of the discrepancies observed in the studies cited above.

In the same way, women with primary amenorrhoea and infertility attributable to a homozygous inactivating mutation in the LH receptor gene, exhibit low concentrations of oestradiol, although ovarian histology reveals all stages of follicular development up to large antral follicles (Latronico et al., 1996Go; Toledo et al., 1996Go). An inherited form of LHß-subunit inactivity was found in a man with hypogonadism (Weiss et al., 1992Go). However, no female sibling was homozygous for the mutation, and the effect of genetic absence of LH on ovarian function is unknown.

GnRH antagonist treatment at high doses can mimic naturally occurring LH deficiencies. In the European Ganirelix Multicentre Dose-Finding Study, the use of GnRH antagonist in the highest dose group (2 mg daily) during ovarian stimulation cycles with rhFSH resulted in profound gonadotrophin suppression, decreased oestradiol concentrations, and shortening of the follicular phase. These observations were accompanied by low implantation (1.5%), and pregnancy rates (3.8%), and higher early miscarriage rates (13%) (Ganirelix Dose-Finding Study Group, 1998Go). Interestingly, these disparate outcomes occurred even though the six different dose groups exhibited a similar number of antral follicles, oocytes recovered, fertilization rates, and numbers of transferable embryos.

Based on these observations, it can be postulated that: (i) follicular development, at least until the pre-ovulatory stage, can occur in the absence of high oestradiol concentrations, and in the absence of significant follicular phase LH bioactivity; (ii) profound LH suppression, and the consequently decreased steroid concentrations, may interfere with optimal oocyte maturation and/or endometrial development.


    Oestrogen actions
 Top
 Abstract
 Introduction
 LH physiology and actions
 Oestrogen actions
 Clinical implications
 Conclusions
 References
 
The common feature of the `experiments of nature' described above, where LH activity is virtually absent, is the very low oestradiol concentration achieved following exogenous FSH administration. Critical extragonadal effects of the rising follicular phase oestrogen concentrations include endometrial growth, adequate cervical mucus, and pituitary priming in preparation for the mid-cycle surge (Shoham et al., 1995Go). At the ovarian level, there is accumulating evidence for autocrine and paracrine actions of oestrogens on the growing follicle cellular compartments and the oocyte. Oestrogen receptor {alpha} (ER{alpha}) is expressed in the human oocyte (Wu et al., 1993Go). Until recently, ER was thought to be absent from both thecal and granulosa cell layers of preantral, pre-ovulatory, and peri-ovulatory follicles in rhesus monkeys (Hild-Petito et al., 1988Go). However, the recent identification of a second ER gene (ERß) (Kuiper et al., 1996Go), as well as its clear predominant expression in the rodent ovary and human GC (Couse et al., 1997Go; Enmark et al., 1997Go), has reopened the debate on the local actions of oestradiol on the developing follicle.

What the mice teach us: the ERß knock-out model
The recent description of female mice lacking ERß might add further information to the role of oestradiol in the ovary (Krege et al., 1998Go). While ERß has a very broad expression pattern, ERß has a more limited expression with notably high levels in the gonad. In the ovaries of the ERß–/– mice, follicles can be seen at all stages of development, ranging from primordial to fully developed antral follicles. However, there are indications of an increased number of atretic follicles, and fewer corpora lutea. Moreover, female ERß–/– mice exhibit reduced fertility, and when ovulation was stimulated, they produce a significantly lower (5-fold) number of oocytes than the wild-type controls. Thus, the relatively mild ovarian phenotype in ERß–/– mice, becomes more dramatic under gonadotrophin stimulation. A functional ERß appears to be necessary for an appropriate oocyte production in rodents. The impact of ovarian stimulation on oestradiol concentrations and embryo viability in this mouse model awaits further investigation. Moreover, the double knock-out (of both ER{alpha} and ERß) mouse, since it is viable, might help us further delineate the importance of oestrogens as growth-promoting factors in the mouse ovary. Although oestrogen actions in the rodent ovary are probably more prominent than those observed in the primate and human ovary, ERß is also the predominant form of ER in the human ovary and is clearly localized in the granulosa cells of maturing follicles (Enmark et al., 1997Go). While the local role of oestrogens in the human ovary has been challenged, further characterization of ERß regulation and function might change our perspective.

Naturally occurring enzymatic defects in oestradiol biosynthesis
The role of oestrogens in follicular development and oocyte maturation is unclear. There have been three published cases of multiple follicular development with exogenous gonadotrophin administration in women harbouring congenital enzymatic deficiencies on the oestrogen steroidogenesis pathway: 17{alpha}-hydroxylase deficiency (Rabinovici et al., 1989Go; Meirow et al., 1996Go), 17–20 desmolase deficiency (Pellicer et al., 1991Go). Despite apparently normal folliculogenesis, oocyte recovery and fertilization, no pregnancy has yet been reported with exogenous FSH alone in such patients. In one of the cases (Rabinovici et al., 1989Go), the two fertilized embryos stopped developing in culture at the 7-cell stage, 75 h after follicular aspiration. The GC collected from this patient showed a decreased capacity to aromatize exogenous androgens, which could be related to the oestradiol or androgen deficiency in the follicular environment (Meirow et al., 1996Go).

Two unrelated females with mutations in the CYP19arom gene have been described, resulting in the total absence of aromatase activity. Large ovarian cysts resembling the PCOS ovarian phenotype have been described in both patients, suggesting that growth of antral follicles can occur in the absence of intra-ovarian oestrogen biosynthesis (Conte et al., 1994Go; Morishima et al., 1995Go).

Evidence from the subhuman primate model
Primate studies have provided considerable information concerning the role of oestrogen in oocyte maturation and fertilizability. The administration of an aromatase inhibitor to gonadotrophin-stimulated macaques in vivo, resulted in an 84% reduction of circulating oestradiol concentrations, but did not affect follicular maturation and pre-ovulatory events (Zelinski-Wooten et al., 1993Go). However, oocytes exposed to high intrafollicular androgen:oestradiol ratios either do not resume meiosis or degenerate. Thus high androgen:oestradiol ratios in the intrafollicular milieu seem detrimental to normal oocyte nuclear maturation in macaques, as was previously suggested in women (McNatty et al., 1979Go). In a second experiment, the same group administered a 3ß-hydroxysteroid dehydrogenase (3ß-HSD) inhibitor to adult rhesus female monkeys undergoing ovarian stimulation with purified human FSH and HMG (Zelinski-Wooten et al., 1994Go). The resulting oestradiol concentrations were as low as 7% of that of the controls throughout the follicular phase. Follicular growth and oocyte nuclear maturity were unaltered by the hypo-oestrogenic milieu. However, the 3ß-HSD inhibition hindered fertilization ability of the metaphase II (15%) and metaphase I in-vitro maturated oocytes (31%) compared with controls. This data suggest that the acquisition of oocyte competence for fertilization may require oestrogens. Finally, the same team examined the developmental potential of embryos produced from GnRH antagonist-treated macaques stimulated with recombinant human FSH (rhFSH), alone or in combination with recombinant human LH (rhLH) (Weston et al., 1996Go). Follicular growth and maturation occurred normally with exogenous rhFSH alone. While multiple follicular growth required a longer interval with rhFSH alone, the total number of follicles did not differ in the presence or absence of rhLH; in the rhFSH alone treatment group more oocytes completed meiosis to metaphase II and fertilized (89 versus 52% in the combination group). The resulting 127 embryos were cryopreserved for subsequent evaluation. There was a significant difference in the embryo viability post-thaw (56 versus 78%), and in the development rate of the blastocysts in culture between the embryos from the rhFSH alone and the rhFSH+rhLH group. Pregnancies occurred following embryo transfer in both groups, one pregnancy out of eight in the rhFSH group, two out of three in the combination group. Thus, FSH alone seems adequate for gametogenic events required to produce embryos; however, exposure to LH (and subsequent oestradiol production) may improve embryo viability post-thaw and increase cleavage rates. Tolerance to cryopreservation could be a valuable marker of the integrity of the embryo's cytoplasmic and membrane compartments. The high fertilization rate seems to indicate that a normal nuclear maturation occurred in the rhFSH alone group. When adequate culture conditions are developed, the blastocyst formation rate could also be a reliable indicator of overall embryo viability. It appears that the development rate also is faster when the follicles are exposed to LH from the beginning of the stimulation protocol, rather than only during the latter phase of the follicular stimulation (Wolf et al., 1989Go). In this study, the endometrial growth cannot account for the observed differences in implantation rates between the two groups, since all the embryos were cryopreserved and then transferred under the same hormonal conditions.

Human oocyte and embryo manipulation in vitro
Oocyte membrane behaviour during intracytoplasmic sperm injection (ICSI) was examined (Palermo et al., 1996Go). The characteristics of the stimulation protocol may well have consequences on the oocyte's membrane and cytoskeletal microtubular structures. Indeed, lower oestradiol concentrations at the time of HCG administration, and shorter length of stimulation were associated with sudden membrane breakage during ICSI, leading to lower oocyte survival and fertilization rates. However, simultaneous studies of the follicular fluid hormonal milieu are necessary to establish a clear relationship between steroid concentrations and oocyte behaviour during in-vitro micromanipulation procedures.

The capacity of the embryo to grow in vitro until the blastocyst stage could be a reliable marker of quality (Meldrum, 1999Go). The outcome of day 5 embryo transfer was studied retrospectively (Schoolcraft et al., 1999Go); two different groups were identified according to the stimulation protocol: pure FSH and FSH in combination with LH and the authors observed that, although the specific protocol had no effect on blastocyst formation, it did have a significant effect on subsequent embryo implantation and pregnancy rates. The inclusion of LH resulted in blastocysts that had a higher developmental potential than blastocysts that were exposed only to FSH. However, these findings require confirmation with a randomized prospective study. In a prospective study of 423 supernumerary embryos no difference was observed in blastocyst formation rates when LH was profoundly suppressed compared with patients having normal serum LH concentrations (Fleming et al., 1998Go).


    Clinical implications
 Top
 Abstract
 Introduction
 LH physiology and actions
 Oestrogen actions
 Clinical implications
 Conclusions
 References
 
From the physiological and basic science data described above, it becomes increasingly clear that some LH activity is essential for optimal maturation and development of the follicle-oocyte unit during ovulation induction treatment. This confirms the `2-cell, two-gonadotrophin' concept, emphasizing that stimulation of both theca cells by LH and granulosa cells by FSH and LH is required for adequate oestradiol biosynthesis (Fevold, 1941Go), but probably also for optimal follicle–oocyte maturation.

Most of the available clinical trials comparing HMG stimulation protocols with purified urinary FSH alone in GnRH agonist-treated patients undergoing IVF treatment are skewed by numerous biases, e.g. inclusion of small numbers of patients, unclear inclusion criteria, heterogenous stimulation protocols, improper randomization and incomplete description of the statistical method. Therefore, these studies cannot ascertain the necessity of including exogenous LH (in the form of HMG or rhLH) in long GnRH agonist protocols. The currently available results from two meta-analyses using the previously cited studies do not seem reliable because they included statistically invalid trials (Daya et al., 1995Go; Loumaye et al., 1997Go). Our review of the literature identified several useful clinical trials showing important outcome differences between the stimulation protocols (Balasch et al., 1996Go; Fleming et al., 1996Go; Soderstrom-Anttila et al., 1996Go; Westergaard et al., 1996Go) (Table I Go).


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Table I. Prospective randomized trials comparing different preparations of gonadotrophins with luteal phase gonadotrophin-releasing hormone agonist (GnRH-a) suppression.
 
The amount of LH activity actually necessary for a normal follicle and oocyte development is not known, but is likely to be very low, since <1% of follicular LH receptors need to be occupied in order to allow normal steroidogenesis (Catt and Dufau, 1977Go; Doerr, 1979Go; Chappel and Howles, 1991Go). In an elegant dose-finding study, the European recombinant human LH study group compared differing rhLH doses which supplemented rhFSH administration for ovulation induction in 34 hypogonadotrophic hypogonadal patients (Recombinant Human LH Study Group, 1998Go). The patients receiving the two highest doses (75 and 225 IU/day of rhLH) had a significantly higher number of large follicles, as well as a higher oestradiol output per follicle, than the two other groups (0 or 25 IU/day of rhLH). Conceptions were achieved only in the highest dose groups of rhLH, while 11 cycles out of 15 had to be cancelled for extremely poor response in the two other groups (Table IIGo). Interestingly, the serum LH concentrations remained below the limit of quantification (1.0 IU/l) in all but three patients who received 225 IU/day of rhLH. Although there are probably individual variations in the dose of LH required to promote optimal follicular development, the majority of patients receiving 75 IU/day of rhLH showed an adequate response, while exhibiting undetectable concentrations of serum LH. Thus, the concentrations of residual endogenous LH remaining during full-dose GnRH agonist pituitary suppression are certainly sufficient to achieve adequate follicular maturation during ovarian stimulation with purified human urinary FSH or recombinant FSH. However, it has been suggested that GnRH agonist down-regulation in some normogonadotrophic women may result in profound suppression of LH concentrations, impairing adequate oestradiol synthesis. Therefore, in cases when pure or recombinant FSH is used for ovarian stimulation after GnRH agonist down-regulation, very low serum LH concentrations may adversely affect IVF outcome. It is possible that some normogonadotrophic women who are profoundly down-regulated with GnRH agonist may benefit from preparations containing LH. In a prospective study, Fleming observed the effect of profound suppression of LH during the follicular phase on the oestradiol serum concentrations and oocyte quality (Table IIIGo) (Fleming et al., 1998Go).


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Table II. Characteristics of hypogonadotrophic hypogonadic patients undergoing rhFSH stimulation with or without rhLH (adapted from European Recombinant Human LH Study Group, 1998)
 

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Table III. Effect of profound suppression of LH concentrations during IVF treatments with purified FSH (adapted from Fleming, 1998)
 
Stimulation protocols including GnRH antagonists
GnRH antagonists offer a new and powerful tool for ovarian stimulation. Administered at pharmacological dosages, they allow an immediate yet completely reversible competitive blockade of the GnRH receptors at the level of the pituitary. In the dose-finding study previously cited (Ganirelix Dose-Finding Study Group, 1998Go), the best outcome was observed with a dose of 0.25 mg/day, starting on day 6 of the stimulation (Table IVGo). This group not only had the highest pregnancy rate, but also the lowest early miscarriage rate, while all groups had the same number of mature oocytes retrieved. Interestingly, LH concentrations throughout the period of antagonist administration, were always detectable (at >1 IU/l), 8 h after the ganirelix injection. This residual endogenous LH activity may have a role in allowing a relatively high oestradiol response (1160 pg/ml) on the day of HCG administration, and may have accounted for the higher ongoing pregnancy and lower miscarriage rates observed. However, it should be emphasized that the relatively low number of patients in each group (n = 60) did not allow any statistically valid comparison. In the near future, it is likely that GnRH antagonists will play an important role in ovulation induction protocols. The ensuing profound suppression of endogenous LH concentrations may necessitate the administration of LH-enriched FSH preparations. Further studies are required to delineate a minimal or optimal LH concentrations or FSH/LH ratios to provide the ideal ovarian stimulation for each patient.


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Table IV. Characteristics of 329 Ganirelix-treated patients undergoing IVF treatment with rhFSH alone (data from Ganirelix Dose-Finding Study Group, 1998)
 
LH and the polycystic ovary
Several studies have attributed detrimental effects to excessive LH in women with PCOS (Chappel and Howles, 1991Go; Shoham et al., 1993Go). Promotion of atresia by LH-induced androgen excess, premature resumption of oocyte meiotic maturation, disruption of GC communication in the cumulus oophorus, and abnormal oocyte maturation are some of the mechanisms that have been postulated to explain both the poor oocyte and embryo quality as well as the reduced fertilization, seen in PCOS patients. However, the administration of HMG to patients with PCOS with or without GnRH agonist suppression, does not result in a significant increase in LH concentrations (Sagle et al., 1991Go; Filicori et al., 1988Go). The LH content of HMG is equal to that of FSH, but the half-life of LH is much shorter than that of FSH, even though some HMG preparations actually contain HCG. Although exogenous FSH is still present 24 h after the injection, LH has been completely eliminated by that time (Yen et al., 1968Go). Thus, daily LH concentrations remain low during HMG administration, while exogenously administered FSH accumulates under GnRH agonist suppression (Filicori, 1999Go).

Studies on GC from PCOS patients in culture suggest that the effect of LH is greatly amplified by the presence of insulin (Willis et al., 1996Go). When the GC are preincubated with insulin, the basal and LH-induced steroid production is significantly increased. Thus, the hyperinsulinaemia often observed in PCOS patients amplifies the ovarian actions of LH concentrations that may already be elevated in these women, by increasing the GC response to LH. Indeed, the effect of LH on the PCOS maturing follicle is similar to that which is exerted at the time of the LH surge (Willis et al., 1996Go). Furthermore, while GC usually respond normally to LH once the follicle reaches 9–10 mm in diameter, GC from anovulatory women with PCOS respond prematurely to LH in smaller follicles of 4 mm (Willis et al., 1998Go).

In summary, LH per se does not appear to have a negative impact on the normal GC. The hypothetical deleterious effects of the high LH concentrations observed in PCOS patients seem to be related to the concomitant hyperinsulinaemia (and/or insulin resistance).


    Conclusions
 Top
 Abstract
 Introduction
 LH physiology and actions
 Oestrogen actions
 Clinical implications
 Conclusions
 References
 
In conclusion: (i) there is no evidence-based clinical argument that the LH content of the available preparations for ovarian stimulation negatively affects the outcome of IVF treatments; (ii) it is possible that a substantial number of normogonadotrophic women are profoundly down-regulated by standard GnRH agonist suppression, and could benefit from the addition of LH to their stimulation protocol; (iii) because there is no reliable or cost-effective way to detect which women will need additional LH administration, it seems practical to systematically add LH to the ovarian stimulation protocols; (iv) new ovarian stimulation strategies are needed, associating purified or recombinant FSH (with an optimal isoform profile) to recombinant LH, HMG or HCG in varying amounts, tailored for the individual patient; and (v) future clinical trials comparing different stimulation protocols should be prospective, randomized and large enough to draw statistically valid conclusions.


    Acknowledgments
 
Delphine P.Lévy and José M.Navarro contributed equally to the manuscript.


    Notes
 
This debate was previously published on Webtrack, July 27, 2000

2 To whom correspondence should be addressed at: The Center For Reproductive Medicine and Infertility, Weill Medical College of Cornell University, New York, New York, USA. E-mail: glschatt{at}mail.med.cornell.edu Back


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 Abstract
 Introduction
 LH physiology and actions
 Oestrogen actions
 Clinical implications
 Conclusions
 References
 
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