1 The Center For Reproductive Medicine and Infertility, Weill Medical College of Cornell University, New York, USA
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Abstract |
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Key words: folliculogenesis/IVF/LH/ovarian stimulation
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Introduction |
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LH physiology and actions |
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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., 1993). However, recent evidence suggests that they may act as growth factors in primate preantral and small antral follicles (Vendola et al., 1998
). Indeed, androgen receptor (AR) mRNA expression is most abundant in GC from healthy preantral and antral follicles in the primate ovary (Hillier et al., 1997
; Weil et al., 1998
), 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., 1998
). 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, 1999
). Indeed, testosterone treatment significantly increases FSH receptor mRNA expression in GC obtained from rhesus monkey follicles at all stages (Weil et al., 1999
). 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., 1999
). 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., 1991), while others have observed no differences (Balasch et al., 1995
). 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., 1991
; Schoot et al., 1994
; Balasch et al., 1995
; Kousta et al., 1996
). More importantly, no pregnancies were observed in these women when they received FSH alone for ovarian stimulation, despite oestradiol replacement (Hull et al., 1994
; Balasch et al., 1995
). 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., 1996; Toledo et al., 1996
). An inherited form of LHß-subunit inactivity was found in a man with hypogonadism (Weiss et al., 1992
). 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, 1998). 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.
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Oestrogen actions |
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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., 1998). 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
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., 1997
). 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-hydroxylase deficiency (Rabinovici et al., 1989
; Meirow et al., 1996
), 1720 desmolase deficiency (Pellicer et al., 1991
). 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., 1989
), 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., 1996
).
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., 1994; Morishima et al., 1995
).
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., 1993). 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., 1979
). 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., 1994
). 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., 1996
). 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., 1989
). 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., 1996). 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, 1999). The outcome of day 5 embryo transfer was studied retrospectively (Schoolcraft et al., 1999
); 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., 1998
).
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Clinical implications |
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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., 1995; Loumaye et al., 1997
). Our review of the literature identified several useful clinical trials showing important outcome differences between the stimulation protocols (Balasch et al., 1996
; Fleming et al., 1996
; Soderstrom-Anttila et al., 1996
; Westergaard et al., 1996
) (Table I
).
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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., 1996). 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., 1996
). Furthermore, while GC usually respond normally to LH once the follicle reaches 910 mm in diameter, GC from anovulatory women with PCOS respond prematurely to LH in smaller follicles of 4 mm (Willis et al., 1998
).
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).
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Conclusions |
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Acknowledgments |
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Notes |
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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
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References |
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