Human Reproduction, Vol. 16, No. 4, 803-804,
April 2001
© 2001 European Society of Human Reproduction and Embryology
Letters to the editor |
LH and ovulation induction
Reproductive Endocrinology Center, Department of Obstetrics and Gynecology, University of Bologna, Via Massarenti 13, 40138 Bologna, Italy E-mail:filicori{at}med.unibo.it
Dear Sir,
Lévy and co-workers (Lévy et al., 2000
) should be commended for publishing a well-written and extensively referenced review article on the role of LH in ovarian stimulation. However, Lévy and co-workers failed to mention in their article some critical physiological and clinical information and relevant literature. One key aspect of the effect of LH activity on the developing follicle is the follicle stimulating hormone (FSH)-mediated acquisition of LH receptors in granulosa cells that occurs in the mid-follicular phase of the normal menstrual cycle, once ovarian follicles reach a diameter of ~10 mm (Zeleznik and Hillier, 1984). At this stage LH can stimulate granulosa cell function and folliculogenesis independently of FSH activity, and the two-cell two-gonadotrophin model is no longer applicable (Hillier et al., 1994).
The ability of LH activity to directly stimulate follicle growth was clearly demonstrated when recombinant human (rh) LH (The European Recombinant Human LH Study Group, 1998) or low-dose human chorionic gonadotrophin (HCG) (Filicori et al., 1999b) were respectively administered to patients with hypogonadotrophic hypogonadism or to GnRH agonist-suppressed women. The expression of LH receptors in mature granulosa cells is a fundamental feature of LH physiology as this is the likely mechanism that allows dominant follicle selection in the mid and late follicular phase of the normal spontaneous menstrual cycle, at a time when serum FSH concentrations decline and LH concentrations increase (Campbell et al., 1999). In addition, Lévy and co-workers also failed to reference studies where rhLH supplementation improved treatment outcome in patients poorly responding to rhFSH administration (Laml et al., 1999) and where a novel regimen of low-dose HCG was used in a hypogonadotrophic patient and greatly boosted her response to highly purified FSH (Filicori et al., 1999a). Finally, after the publication of Lévy and co-workers, we reported an improved clinical response and optimization of folliculogenesis [reduction of small-sized ovarian follicles, that tend to be associated with the occurrence of ovarian hyperstimulation syndrome (OHSS)] when HMG was compared to highly purified FSH in GnRH agonist-suppressed patients (Filicori et al., 2001).
Thus, the evidence summarized in the article by Lévy and co-workers and in the papers referenced in this letter points towards a positive action of LH exerted on follicle/oocyte development and ovulation induction not only through provision of androgen substrate and enhanced oestrogen concentrations but also through a direct effect on the stimulation and modulation of folliculogenesis. This information is critical for optimizing ovulation induction regimens and may help us when designing new ovarian stimulation protocols potentially associated with reduced risks of multiple conceptions and of OHSS. Furthermore, although recombinant gonadotrophins represent elegant tools to provide selective hormone activity, we clearly demonstrated (Filicori et al. 1999a,b; 2001) that urinary-derived gonadotrophin preparations such as HCG and HMG can offer an effective, widely available, and less costly alternative to rhLH or rhHCG when LH activity supplementation is desirable.
References
Campbell, B.K., Dobson, H., Baird, D.T. et al. (1999) Examination of the relative role of FSH and LH in the mechanism of ovulatory follicle selection in sheep. J. Reprod. Fertil., 117, 355–367.
Filicori, M., Cognigni, G.E., Taraborrelli, S. et al. (1999a) Low-dose human chorionic gonadotropin therapy can improve sensitivity to exogenous follicle-stimulating hormone in patients with secondary amenorrhea. Fertil. Steril., 72, 1118–1120.[Web of Science][Medline]
Filicori, M., Cognigni, G.E., Taraborrelli, S. et al. (1999b) Luteinizing hormone activity supplementation enhances follicle-stimulating hormone efficacy and improves ovulation induction outcome. J. Clin. Endocrinol. Metab., 84, 2659–2663.
Filicori, M., Cognigni, G.E., Taraborrelli, S. et al. (2001) Luteinizing hormone activity in menotropins optimizes folliculogenesis and treatment in controlled ovarian stimulation. J. Clin. Endocrinol. Metab., 86, 337–343.
Hillier, S.G., Whitelaw, P.F., and Smyth, C.D. (1994) Follicular oestrogen synthesis: the `two-cell, two-gonadotrophin' model revisited. Mol. Cell. Endocrinology, 100, 51–54.[Web of Science][Medline]
Laml, T., Obruca, A., Fischl, F. et al. (1999) Recombinant luteinizing hormone in ovarian hyperstimulation after stimulation failure in normogonadotropic women. Gynecol. Endocrinology, 13, 98–103.[Web of Science][Medline]
Lévy, D., Navarro, J.M., Schattman, G.L. et al. (2000) The role of LH in ovarian stimulation. Exogenous LH: let's design the future. Hum. Reprod., 15, 2258–2265.
The European Recombinant Human LH Study Group (1998) Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. J. Clin. Endocrinol. Metab., 83, 1507–1514.
Zeleznik, A.J. and Hillier, S.G. (1984) The role of gonadotropins in the selection of the preovulatory follicle. Clin. Obstet. Gynecol., 27, 927–940.[Web of Science][Medline]
Center for Reproductive Medicine and Infertility, Cornell University Medical College, HT-330, 505 East-70th Street, New York, NY 10021, USA
Dear Sir,
We appreciate Dr Filicori's interest in our publication and welcome comments from someone who has contributed much to our understanding of human menstrual physiology. The purpose of our review was to discuss the role of LH in follicular growth and development and also oocyte and embryo quality. While LH is able to sustain or even enhance follicular growth once the follicle has reached a certain size and competency, the initial development and follicle selection is exclusively dependant on follicle stimulating hormone (FSH). Dr Filicori's first point regarding the FSH mediated acquisition of LH receptors on granulosa cells is prominently stated in the first paragraph of our article on LH physiology, and clearly represented in Figure 1 of our article. The fact that LH alone is able to sustain follicular development and oestradiol production after, and only after adequate FSH priming (Hillier et al., 1994; Sullivan et al., 1999) is physiologically interesting, but oocyte quality or pregnancy rates have never been evaluated in large numbers of subjects. Because FSH concentrations normally decline during spontaneous cycles with rising oestradiol concentrations, the relative role of FSH as the cycle progresses can be expected to diminish. Our purpose was in fact to clarify whether or not the addition of LH to ovarian stimulation protocols was beneficial in terms of oocyte and embryo quality; or conversely, if excessive amounts of LH in certain circumstances might have detrimental effects on the follicle/oocyte unit and subsequent outcome. We attempted to analyse the literature on this controversial subject from an experimental point of view, rather than a purely descriptive one.
Based on the available data, we cannot agree with the comment that `expression of LH receptors in mature granulosa cells is the likely mechanism that allows dominant follicle selection'. The current theory rather favours the concept that selection of the dominant follicle in humans is the consequence of an increasing FSH sensitivity, specific to the largest (or most competent) follicle, which despite declining concentrations of FSH continues to grow until preovulatory size, and maintains its capacity to aromatize androgens efficiently (Adashi, 1995). The mechanisms of this improved FSH sensitivity remain unclear, hypotheses have been formulated involving ovarian peptides such as inhibins and activins, as well as locally produced androgens (Hillier, 1999).
Concerning the direct LH stimulation of follicular growth, the European Recombinant Human LH study group clearly showed that the FSH priming of early follicular events is a pre-requisite for the acquisition of LH responsiveness, and whilst LH can enhance FSH action and sustain later stages of follicular development, it cannot do so at an earlier stage. The fact that LH supplementation does improve outcome in poor responders to pure FSH protocols is actually mentioned several times in our publication (Shoham et al., 1991; Schoot et al., 1994; Balasch et al., 1995; Ganarelix Dose Finding Group, 1998; European Recombinant Human LH Study Group, 1998). The fact that the timely addition of LH to ovulation induction protocols could prevent multiple gestations or ovarian hyperstimulation syndrome has been suggested by recent experimental studies on small groups of patients, and remains to be validated on a larger scale (Sullivan et al., 1999).
Lastly, while we did not imply in our publication that recombinant LH is the only or best option for LH replacement in those patients requiring LH supplementation, it can be considered as a tool, along with recombinant FSH, in hypogonadal patients in an attempt to define the amount and timing of LH necessary for optimal oocyte maturation. Clearly, urinary human menopausal gonadotrophin (HMG) offers effective treatments for these patients. However, fixed ratios of FSH:LH, and additional impurities have rendered the interpretation of the clinical studies comparing HMG to purified or recombinant preparations very questionable. We agree that HMG can be an appropriate and cheaper way to treat our patients. While LH supplementation might not be necessary for all patients, based on available data, it does not appear to be harmful in the small doses used (we usually do not exceed 150 IU of HMG in our regimens). For the majority of patients, cheap recombinant LH, with reliable bioactivity and amount, and devoid of urinary impurities, could represent our most flexible solution.
References
Adashi, E.A. (1995) The ovarian follicle:Life cycle of a pelvic clock. In Adashi, E.A., Rock, Rosenwaks (eds). Reproductive Endocrinology, Surgery, and Technology. Lippincott-Raven, Philadelphia, PA, USA. pp. 212–234
Balash, J., Miro, F., Burzaco, I. et al. (1995) The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone. Hum. Reprod., 10, 1678–1683.
European Recombinant Human LH Study Group (1998) Recombinant human luteinization hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. J. Clin. Endocrinol. Metab., 83, 1507–1514.
Ganarelix Dose Finding Group (1998) A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotropin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon®). Hum. Reprod., 13, 3023–3031.
Hillier S.G., Whitelaw P.F. and Smyth, C.D. (1994) Follicular estrogen synthesis: The `two-cell, two-gonadotrophin' model revisited. Mol. Cell. Endocrinology, 100, 51–54.
Hillier S.G. (1999) Role of androgens in ovarian folliculogenesis. In Filicori, M. (ed) The Role of Luteinizing Hormone in Folliculogenesis and Ovulation Induction. Monduzzi Ed, Bologna, Italy, 69–78.
Lévy, D., Navarro, J.M., Schattman, G.L. et al. (2000) The role of LH in ovarian stimulation. Exogenous LH: let's design the future. Hum. Reprod., 15, 2258–2265.
Schoot, D. C., Harlin, J., Shoham, Z. et al. (1994) Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women. Hum. Reprod., 9, 1237–1242.
Shoham, Z., Balen, A., Patel, A. and Jacobs, H.S. (1991) Results of ovulation induction using human menopausal gonadotropin or purified follicle-stimulating hormone in hypogonadotropic hypogonadism patients. Fertil. Steril., 56, 1048–1053.[Web of Science][Medline]
Sullivan, M.W., Stewart-Akers, A., Krasnow, J.S. et al. (1999) Ovarian responses in women to recombinant follicle stimulating hormone and luteinizing hormone (LH): a role for LH in the final stages of follicular maturation. J. Clin. Endocrinol Metab., 84, 228–232.
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