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Current concepts and novel applications of LH activity in ovarian stimulation
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Current concepts and novel applications of LH activity in ovarian stimulation Marco Filicori, Graciela E. Cognigni, Patrizia Pocognoli, Walter Ciampaglia and Silvia Bernardi Reproductive Endocrinology Center, University of Bologna, Via Massarenti 13, 40138 Bologna, Italy
Luteinizing hormone (LH) is a crucial physiological regulator of the human menstrual cycle. LH activity is also contained in many medications used to treat anovulation and to stimulate multiple folliculogenesis for assisted reproduction techniques. However, LH activity had previously been regarded as just a contaminant of follicle-stimulating hormone (FSH)-containing products and deemed potentially detrimental for reproductive function. Novel experimental and clinical evidence now suggests that the administration of pharmacological amounts of LH activity, instead of being harmful, is therapeutically advantageous, particularly in the support and modulation of ovarian folliculogenesis. The aim of this article is to provide an overview of the effects of LH activity administration in ovarian stimulation and to outline novel unconventional gonadotropin regimens that might improve the efficacy, safety and convenience of ovulation induction. Medications that restore or therapeutically modify the ovulatory process have been used for over four decades in the management of menstrual cycle disorders and for the treatment of infertility. Ovulation induction can be applied to treat anovulation or to stimulate multiple folliculogenesis in patients who are candidates for assisted reproduction technology (ART), a procedure also termed controlled ovarian stimulation (COS). Complications can occur during exogenous gonadotropin administration, including multiple gestations and the ovarian hyperstimulation syndrome (OHSS). With some notable exceptions, such as the use of gonadotropin-releasing hormone (GnRH) analogs, gonadotropin administration regimens have not greatly changed since the 1960s, and still rely on the capacity of these medications to overcome and disrupt the normal hormonal control mechanisms of the spontaneous menstrual cycle to force the ovary to produce one or more reproductively competent follicles and oocytes. The use of novel therapeutic regimens that more closely mimic the hormonal dynamics of the spontaneous menstrual cycle might enable us to improve this form of therapy through a greater control of folliculogenesis. Corresponding author: M. Filicori ([email protected]).
Gonadotropin actions on ovarian follicles Theca cells Luteinizing hormone (LH) stimulates theca cell (TC) androgen production; LH receptors are present on TCs from fetal life (Table 1). TC androgens are transferred into granulosa cells (GCs) and turned into estrogens through the catalytic action of the aromatase system; folliclestimulating hormone (FSH) alone induces the aromatase system in small antral follicular GCs. This modular action of gonadotropins was named the ‘two cell-two gonadotropin model’ [1]. GC-produced estrogens play a fundamental role in the reproductive system by improving follicle and oocyte maturity, priming the hypothalamic – pituitary unit and inducing the morphological uterine and endometrial changes needed for embryo implantation. Granulosa cells The capacity of LH to interact with ovarian GCs is dependent upon the development of specific LH receptors by these cells (Table 1). During the follicular phase, FSH stimulates GCs to express LH receptors [2]; this action is facilitated by estrogens. Thus, in the late stages of follicle development, GCs become responsive to LH, which can exert virtually all of the physiological actions of FSH on GCs, including the stimulation of the aromatase system [3]. Because of these events, the two cell-two gonadotropin model is not fully applicable throughout the entire lifespan of the ovarian follicle and must be revised and reassessed at least for the late part of GC functional life [4]. The rise in serum FSH levels typical of the luteal – follicular transition is crucial for stimulating ovarian follicle recruitment. Conversely, the reduced FSH levels in Table 1. The occurrence of FSH and LH receptors in the theca and granulosa cells of the human ovary at different stagesa Stage of life
Theca cell receptors FSH
LH
Granulosa cell receptors FSH LH
Prenatal Prepubertal Adult menstrual cycle Early follicular Mid- to late-follicular
2 2
þ þ
þ þ
2 2
2 2
þ þ
þ þ
2 þ
a
Abbreviations: FSH, follicular stimulating hormone; LH, luteinizing hormone.
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the remaining part of the follicular phase prevent the further emergence of immature follicles, whereas progressively increasing LH levels support the growth and maturation of the dominant follicle. Almost two decades ago it was suggested that FSH stimulation might not be required once GCs express adequate amounts of LH receptors [3]; this concept was recently tested and confirmed in humans [5– 7]. The expression of GC LH receptors enables the larger follicle(s) to keep growing and to develop dominance over smaller follicles, the GCs of which are devoid of LH receptors [8]. This dynamic interplay of serum gonadotropin secretion and receptor expression by different ovarian cells enables the uninterrupted progression of folliculogenesis to occur from a large pool of immature follicles, until ovulation of a single dominant follicle. These changes in receptor expression are also the basis for the mechanism of action of gonadotropin administration during ovulation induction. Use of LH activity to treat anovulation Gonadotropin medications used for ovulation induction and COS are listed in Table 2. Traditional human menopausal gonadotropin (hMG) contains 75 IU of FSH combined with 75 IU of LH activity or less. A new highly purified (HP) formulation of hMG that can be administered subcutaneously is now also available [9]. Human chorionic gonadotropin (hCG) also contributes to the LH activity of menotropins [10]. Limited published data exist on the specific effects of the administration of different forms of LH activity; however, hCG potency appears to be approximately six times greater than that of LH [11]. Gonadotropin preparations devoid or with highly reduced LH activity include human FSH (hFSH), HP FSH, and recombinant FSH (rFSHa and rFSHb), whereas only LH activity is contained in recombinant LH (rLH), hCG and recombinant chorionic gonadotropin (rCG). Treatment of hypogonadotropic hypogonadism Reduced gonadotropin levels in hypogonadotropic hypogonadism (HH) are mostly related to a deficit of GnRH
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secretion. Although HH patients tend to respond well to gonadotropins, combined FSH and LH activity administration appears to be necessary in this condition [12]. FSHonly administration requires greater gonadotropin doses and results in fewer preovulatory follicles, lower estradiol (E2) levels, and reduced endometrial thickness and incidence of ovulation [13 – 15]. Oocyte quality might also be affected by LH activity deprivation because reduced oocyte fertilization occurred after HP FSH treatment [16]. Serum estrogen levels and folliculogenesis were positively correlated with the amount of rLH administered during rFSH administration [17]. Low-dose hCG or rCG can also be used to supply LH activity to HH patients; controlled ovarian stimulation was shortened and the HP FSH dose was reduced after the addition of 50 IU d21 of hCG [18]. A combined regimen of rFSH (75 IU d21) and rCG (2.5 mg d21) in one HH patient resulted in E2 increments, the development of a dominant follicle and pregnancy [19]. Thus, LH activity supplementation in HH patients improves gonadal steroid biosynthesis, follicle development, endometrial thickness, treatment parameters (duration and gonadotropin dose) and overall therapeutic success of ovulation induction. Treatment of polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is often associated with high endogenous LH secretion, menstrual cycle disorders, infertility and high rates of spontaneous abortion. Excessive LH levels stimulate theca cell androgen secretion and could be involved in small follicle atresia. It was suggested that LH might directly or indirectly hasten late follicular phase meiotic maturation through disruptions of GC communication in the cumulus oophorus [20]. Nevertheless, the success of ART is not reduced in PCOS because the number and quality of oocytes and embryos is at least as good (and often superior) to those of control subjects [21]. Furthermore, convincing evidence is being accrued to suggest a close link between the reproductive system defects of PCOS and hyperinsulinemia [22]. Metformin administration restored the response of PCOS patients to
Table 2. Types, gonadotropin content and brand names of gonadotropin preparations currently available in European countries and North Americaa,b Type of gonadotropin Human derived HP FSH hFSH hMG hMG HP hMG Recombinants rFSHa rFSHb rLH Chorionic gonadotropins hCG rCG a
Gonadotropin activity content per ampoule/vial FSH LH
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75 IU 75 IU 75 IU 75 IU 75 IU
, 0.1 IU , 1 IU 25 –35 IU 75 IU 75 IU
Metrodin HP, Bravelle Metrodin, Fostimon Normegon, Pergogreen Pergonal, Humegon, Menogon, Repronex Menopur
37.5– 1200 IU 50– 200 IU A
A A 75 IU
Gonal F Puregon, Follistim Luveris
A A
CG 250 –5000 IU CG 250 mg
Profasi, Gonasi, Novarel, Choragon, Pregnyl Ovidrel
Abbreviations: A, absent; CG, chorionic gonadotropin; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; hFSH, human follicle-stimulating hormone; hMG, human menopausal gonadotropin; HP FSH, highly purified follicle-stimulating hormone; HP hMG, highly purified human menopausal gonadotropin; LH, luteinizing hormone; rCG, recombinant chorionic gonadotropin; rFSHa, recombinant follicle-stimulating hormone a; rFSHb, recombinant follicle-stimulating hormone b; rLH, recombinant luteinizing hormone. b Drug formulations and brand names might differ in some countries. http://tem.trends.com
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clomiphene citrate [23], and normalized estrogen levels and follicle response during gonadotropin administration, possibly through a reduction of GC aromatase activity [24], and was associated with dramatic improvements in the occurrence of spontaneous and recurrent abortion [25,26]. Although additional evidence obtained through randomized controlled trials will be needed before metformin is applied routinely [27], hyperinsulinemia rather than increased LH secretion per se appears to be the key factor in the pathogenesis of reproductive system dysfunctions in PCOS. Early investigations showed no difference [28] in ovulatory and pregnancy rates between hMG and hFSH [29]; the number of follicles and the occurrence of ovarian hyperstimulation were actually greater after hFSH. Twelve PCOS patients were assessed by Larsen et al. [30] in a randomized, double blind, crossover study that compared hFSH and hMG; no significant treatmentrelated differences were found in the variables assessed. A larger study comprising 30 PCOS patients also failed to detect an advantage in the use of hFSH versus hMG administered in a low-dose regimen [31]. A lack of improvements in pregnancy rates of FSH-only administration over hMG in PCOS ovulation induction was recently confirmed by two Cochrane meta-analyses of randomized controlled trials [32,33]. Thus, LH activity administration through hMG does not appear to be detrimental to ovulation induction in PCOS. Use of LH activity in assisted reproduction Larger amounts of exogenous gonadotropins are used to achieve the high oocyte recovery yields needed for ART procedures. Although most of the gonadotropin preparations listed in Table 2 are used in clinical practice, no agreement exists regarding exact treatment regimens and protocols. One heated debate regards the possibility that LH activity-containing preparations might provide better and more efficient results than the administration of FSH-only products; however, few studies have systematically addressed this issue. Retrospective meta-analyses comparing LH-containing regimens with LH-free stimulation regimens have provided conflicting results [34– 36]. Is there a threshold and ceiling for LH activity? It has been suggested that a ‘threshold’ and a ‘ceiling’ might exist in LH activity, (i.e. an optimal range for LH action), and that excessive LH activity administration might negatively affect treatment outcome in ovulation induction and ART [37]. The presence of low baseline LH concentrations is associated with HH or the suppressive action of GnRH agonists in otherwise normal patients. Women with low endogenous LH secretion respond better to ovulation induction when both FSH and LH activity are administered [38,39]. Furthermore, patients with intermediate levels of residual endogenous LH secretion on stimulation day 8 were found to respond optimally, whereas women with higher or lower LH concentrations had reduced success rates in ART [40]. Although it was suggested that patients with less profound suppression of endogenous gonadotropins might not benefit from LH supplementation, these negative findings might be related http://tem.trends.com
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to the modest amounts of LH activity administered (rLH, 25–150 IU d21) [41,42]. Recent studies also suggested that the administration of even small amounts of LH activity could be detrimental to embryo quality and implantation in some patients [40,43]. These findings conflict with other studies that failed to demonstrate such negative effects of LH [44], and other investigations that actually suggested a positive action of LH activity on implantation [45] and miscarriage prevention [38,46]. The use of 150 IU d21 of LH activity given as HP hMG did not cause untoward effects in ART [47], and in our experience even the administration of much larger amounts of LH activity (e.g. hCG 200 IU d21, corresponding to 1,200 IU d21 of LH) did not hamper the reproductive potential of ART patients [7]. The apparent contradiction of these studies might be related to a selection bias in the patients who ended up responding worse to LH activity administration. Thus, it appears that, although LH activity should always be administered in conditions of profound endogenous LH suppression (the threshold concept), evidence in support of the existence of a ceiling of LH activity is controversial, at least within the drug regimens currently used in ART [48]. Oocyte/embryo quality and follicular environment Disagreement exists regarding oocyte and embryo quality obtained with different gonadotropin regimens. Early studies [49] found a higher percentage of mature oocytes in patients treated with human-derived FSH than in patients receiving hMG or a combination of these gonadotropins [50]. Conversely, more recent reports provided conflicting results [42], or could not identify a significant difference in metaphase II oocytes between treatment with hMG and with human-derived FSH [51] or rFSH [44,52]; embryo quality was also comparable [44]. Furthermore, implantation rates were found to be positively correlated with the LH activity dose administered [45], and LH activity dramatically improved implantation and pregnancy rates following blastocyst transfer [46]. Higher follicular fluid content of LH at the time of oocyte retrieval was associated with improved embryo quality [53,54]. Even in PCOS patients (who have high endogenous LH secretion), mature oocyte yield and cleavage rates were similar in hMG and hFSH-treated patients [55] and no significant differences in ART outcome (oocyte maturity and fertilization rates) were found when rFSH and hMG were compared [56]. Premature luteinization Although serum progesterone (P) levels are usually low during gonadotropin administration in ART patients, moderate serum P increments (usually 1 – 3 ng/ml) can occasionally be seen during COS [57,58] and were thought to be caused by GC luteinization of developing follicles induced by premature LH increments or the hCG content of hMG [59]. These small P increments are not detrimental to oocyte or embryo quality [60 – 63], but it was suggested that they might reduce ART success through secretory endometrial transformations that hamper embryo implantation [64]. Profound endogenous LH suppression with GnRH agonists [63,65] or GnRH antagonists [66], and the use of FSH-only preparations [63] failed to eliminate
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Fig. 1. Correlation between serum progesterone (P) levels during ovulation induction and the total amounts of (a) follicle-stimulating hormone (FSH) activity and (b) luteinizing hormone (LH) activity administered to each patient. P levels were determined daily throughout gonadotropin administration in each patient and expressed as area under the curve. Reproduced, with permission, from [69].
premature luteinization. Furthermore, hMG administration [67] or FSH supplementation with 50 IU d21 of hCG [68] did not significantly affect serum P levels. In a recent larger study [69], the LH activity dose administered was found to be unrelated to serum P levels; conversely, a positive and highly significant correlation was found between the FSH dose administered and serum P levels (Fig. 1). Finally, even larger amounts of LH activity did not greatly affect P secretion [6,7]. This information points towards FSH, rather than LH and hCG, as the causative agent of P increments during COS [63]. Such an interpretation was supported by our recent finding that rFSH (a more active stimulator of GC function than human-derived FSH) was associated with higher P concentrations during COS [47]. Thus, the term ‘premature luteinization’ appears to be a misnomer because moderate follicular phase P increments seem to reflect greater FSH-induced GC steroidogenetic activity; this phenomenon might be reduced by lowering the amount of FSH used in ovulation induction. Because LH activity co-administration permits the curtailment of
Preovulatory follicles <10mm
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the FSH dose used in COS [40,67,68], LH activity-rich regimens could limit rather than cause ‘premature luteinization’. Modulation of folliculogenesis The degree and quality of folliculogenesis achieved through COS appears to be affected by different gonadotropin preparations. Following FSH priming, LH activity can support and stimulate the growth of large antral follicles [6,7] through its interaction with GC LH receptors. Conversely, hMG administration leads to a progressive decline in the number of small (, 10 mm) ovarian follicles [67]. FSH alone enhances, whereas LH decreases, the number of small (, 10 mm) preovulatory follicles (Fig. 2) [69]; this effect can be brought about by very small amounts of LH activity (e.g. 37.5 IU d21) [6]. Although this reduction in small preovulatory follicles could also be the result of the lower FSH doses administered, the finding that this phenomenon also occurs when FSH is maintained at a constant level suggests a specific LH-related effect [6]. (b)
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Fig. 2. Correlation between the number of small preovulatory follicles (, 10 mm diameter) and the total amounts of (a) follicle-stimulating hormone (FSH) and (b) luteinizing hormone (LH) activity administered to each patient. Reproduced, with permission, from [69]. http://tem.trends.com
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Novel LH activity administration regimens Recent findings suggest that LH activity administration can be extremely effective in the late stages of ovulation induction and COS, and can support ovarian follicle development even in the absence of FSH administration. Sullivan et al. [5] found that replacement of rFSH with rLH (150 or 375 IU, twice daily) at the end of COS prevented the E2 decline associated with rFSH discontinuation. After one week of ovarian priming with rFSH, we treated GnRH agonist-suppressed patients with various combinations of rFSH and low-dose hCG; most patients completed treatment with comparable numbers of large preovulatory follicles and serum E2 levels, even when exogenous FSH was completely discontinued [6]. Finally, when an eight-day course of hMG was followed by five days of low-dose hCG alone, E2 levels and the growth of large ovarian follicles continued to increase (Fig. 3); several mature oocytes were retrieved and pregnancy was achieved with intracytoplasmic sperm injection [7]. We suggested that these features could be applied to COS by providing an FSH prevalent stimulation in the early stages of treatment to enhance follicle recruitment, followed by an LH prevalent stimulation to support selectively the development of larger and reproductively competent follicles [48,73]; in addition to reducing FSHrelated costs, these regimens might provide a means of achieving better and safer COS by increasing follicular fluid estrogen concentrations (and hence oocyte quality), and reducing the occurrence of small preovulatory follicles that might predispose patients to the development of OHSS.
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FSH-only versus combined FSH and LH activity administration Patients treated with hMG have higher serum LH, hCG and E2 levels and fewer small (, 10 mm diameter) preovulatory ovarian follicles than patients receiving HP FSH or rFSH [67,70]. Furthermore, we recently found that serum immunoreactive FSH levels are significantly increased after hMG and HP hMG administration versus rFSH [47,70]; this feature is probably related to the different FSH isoforms found in human-derived and recombinant products. Oocyte and embryo quality, pregnancy rates and pregnancy outcome did not differ when rFSH was compared with hMG [71] or HP hMG [9]; this finding was confirmed by a recent meta-analysis [35]. Pregnancy rates and ovulation induction complications were similar when rFSHa was compared with hMG [70] or HP hMG [47]; however, treatment duration and the gonadotropin dose used were significantly increased in patients treated with rFSHa in both studies. Supplementation of HP FSH 150 IU d21 with 50 IU d21 of hCG hastened large follicle development and reduced treatment duration and the HP FSH dose needed to achieve comparable folliculogenesis and serum E2 levels [68]. Co-administration of rFSH and rCG (2.5 mg d21, roughly corresponding to 300 IU d21 of LH) in subjects undergoing COS for oocyte donation resulted in higher preovulatory E2 levels and a significantly greater number of oocytes and embryos available for cryopreservation [72].
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Fig. 3. Daily serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG), estradiol (E2), progesterone (P) and testosterone (T) and the number of large ((a) .14 mm diameter], intermediate [(b) 10 –14 mm] and small [(c) ,10 mm] ovarian follicles detected at transvaginal pelvic ultrasound during ovulation induction in a patient undergoing intracytoplasmic sperm injection. human menopausal gonadotropin (hMG) was administered at a dose of 225 IU d21 until treatment day 7 and then discontinued; thereafter, hCG (200 IU d21) was given alone to support follicular growth for five days. On the last ultrasound, 15 large, one intermediate and two small follicles were detected. This patient conceived and carried to term a twin pregnancy. Reproduced, with permission, from [7].
Conclusions Ovarian induction remains a key therapeutic step in the management of infertile couples. Current ovarian stimulation techniques are almost completely focused on FSH and tend to disregard the key role played by LH in menstrual cycle physiology; the non-detrimental or frankly positive outcome of LH activity administration in several published studies suggests that the use of LH activity should be expanded. LH stimulation shortens FSH treatment, reduces FSH dose requirements, does not cause premature follicle luteinization and improves the last ovarian stimulation stages by limiting the development of small antral follicles. Nevertheless, it is also evident that
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this field remains controversial and that additional studies and randomized controlled trials should be carried out to clarify and define the clinical benefits and possible drawbacks of LH activity administration during COS. The most challenging concept in this area is related to the demonstration that the development of the more mature ovarian follicles can be stimulated by the sole administration of LH activity. Much remains to be done to devise clinically suitable gonadotropin regimens based on this principle; randomized controlled trials that assess the merits of these treatment Scheme in ART are not yet available. Nevertheless, once therapeutic efficacy is confirmed, this approach might enable us to reduce the costs and complications of infertility treatment.
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Acknowledgements We thank Nadia Torcoletti for preparation of the manuscript. M.F. is a scientific advisor to Ferring Pharmaceuticals.
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stimulation in normogonadotrophic women undergoing assisted reproduction. Hum. Reprod. 15, 1003 – 1008 Westergaard, L.G. et al. (2001) Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotropic women down-regulated with a gonadotropin-releasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil. Steril. 76, 543 – 549 Humaidan, P. et al. (2002) Ovarian response and pregnancy outcome related to mid-follicular LH levels in women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH stimulation. Hum. Reprod. 17, 2016– 2021 Sills, E.S. et al. (1999) A prospective, randomized comparison of ovulation induction using highly purified follicle-stimulating hormone alone and with recombinant human luteinizing hormone in in-vitro fertilization. Hum. Reprod. 14, 2230 – 2235 Balasch, J. et al. (2001) The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction. J. Assist. Reprod. Genet. 18, 250 – 256 Tesarik, J. and Mendoza, C. (2002) Effects of exogenous LH administration during ovarian stimulation of pituitary down-regulated young oocyte donors on oocyte yield and developmental competence. Hum. Reprod. 17, 3129– 3137 Ng, E.H. et al. (2001) HMG is as good as recombinant human FSH in terms of oocyte and embryo quality: a prospective randomized trial. Hum. Reprod. 16, 319– 325 Gordon, U.D. et al. (2001) A randomized prospective assessor-blind evaluation of luteinizing hormone dosage and in vitro fertilization outcome. Fertil. Steril. 75, 324– 331 Schoolcraft, W.B. et al. (1999) Blastocyst culture and transfer: analysis of results and parameters affecting outcome in two in vitro fertilization programs. Fertil. Steril. 72, 604 – 609 Kilani, Z. et al. A prospective, randomised, controlled trial comparing HP HMG to recombinant FSH in women undergoing ICSI: ovarian response and clinical outcomes. Hum. Reprod. (in press) Filicori, M. (2003) Use of luteinizing hormone in the treatment of infertility: time for reassessment? Fertil. Steril. 79, 253 – 255 Mercan, R. et al. (1997) Improved oocyte quality is obtained with follicle stimulating hormone alone than with follicle stimulating hormone/human menopausal gonadotrophin combination. Hum. Reprod. 12, 1886 – 1889 Imthurn, B. et al. (1996) Nuclear maturity and oocyte morphology after stimulation with highly purified follicle stimulating hormone compared to human menopausal gonadotrophin. Hum. Reprod. 11, 2387 – 2391 Weissman, A. et al. (1999) Intracytoplasmic sperm injection after follicle stimulation with highly purified human follicle-stimulating hormone compared with human menopausal gonadotropin. J. Assist. Reprod. Genet. 16, 63 – 68 Agrawal, R. et al. (1998) Implications of using follicle-stimulating hormone preparations depleted of luteinizing hormone to achieve follicular growth in in vitro fertilization. Gynecol. Endocrinol. 12, 9 – 15 Mendoza, C. et al. (1999) Relationship between fertilization results after intracytoplasmic sperm injection, and intrafollicular steroid, pituitary hormone and cytokine concentrations. Hum. Reprod. 14, 628 – 635 Mendoza, C. et al. (2002) Follicular fluid markers of oocyte developmental potential. Hum. Reprod. 17, 1017 – 1022 Tanbo, T. et al. (1990) Stimulation with human menopausal
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gonadotropin versus follicle-stimulating hormone after pituitary suppression in polycystic ovarian syndrome. Fertil. Steril. 53, 798 – 803 Teissier, M.P. et al. (1999) Recombinant human follicle stimulating hormone versus human menopausal gonadotrophin induction: effects in mature follicle endocrinology. Hum. Reprod. 14, 2236 – 2241 Fanchin, R. et al. (1993) Premature elevation of plasma progesterone alters pregnancy rates of in vitro fertilization and embryo transfer. Fertil. Steril. 59, 1090– 1094 Silverberg, K.M. et al. (1991) Serum progesterone levels predict success of in vitro fertilization/embryo transfer in patients stimulated with leuprolide acetate and human menopausal gonadotropins. J. Clin. Endocrinol. Metab. 73, 797– 803 Copperman, A.B. et al. (1995) Relationship between circulating human chorionic gonadotropin levels and premature luteinization in cycles of controlled ovarian hyperstimulation. Fertil. Steril. 63, 1267 – 1271 Chetkowski, R.J. et al. (1997) In premature luteinization, progesterone induces secretory transformation of the endometrium without impairment of embryo viability. Fertil. Steril. 68, 292 – 297 Hofmann, G.E. et al. (1993) Premature luteinization in controlled ovarian hyperstimulation has no adverse effect on oocyte and embryo quality. Fertil. Steril. 60, 675 – 679 Legro, R.S. et al. (1993) Premature luteinization as detected by elevated serum progesterone is associated with a higher pregnancy rate in donor oocyte in-vitro fertilization. Hum. Reprod. 8, 1506 – 1511 Ubaldi, F. et al. (1996) Premature luteinization in in vitro fertilization cycles using gonadotropin-releasing hormone agonist (GnRH-a) and recombinant follicle-stimulating hormone (FSH) and GnRH-a and urinary FSH. Fertil. Steril. 66, 275 – 280 Shulman, A. et al. (1996) The significance of an early (premature) rise of plasma progesterone in in vitro fertilization cycles induced by a “long protocol” of gonadotropin releasing hormone analogue and human menopausal gonadotropins. J. Assist. Reprod. Genet. 13, 207– 211 Hofmann, G.E. et al. (1993) Premature luteinization is not eliminated by pituitary desensitization with leuprolide acetate in women undergoing gonadotrophin stimulation who demonstrated premature luteinization in a prior gonadotrophin-only cycle. Hum. Reprod. 8, 695– 698 Ubaldi, F. et al. (1996) Subtle progesterone rise after the administration of the gonadotrophin-releasing hormone antagonist cetrorelix in intracytoplasmic sperm injection cycles. Hum. Reprod. 11, 1405– 1407 Filicori, M. et al. (2001) Luteinizing hormone activity in menotropins optimizes folliculogenesis and treatment in controlled ovarian stimulation. J. Clin. Endocrinol. Metab. 86, 337 – 343 Filicori, M. et al. (1999) Luteinizing hormone activity supplementation enhances follicle-stimulating hormone efficacy and improves ovulation induction outcome. J. Clin. Endocrinol. Metab. 84, 2659 – 2663 Filicori, M. et al. (2002) Modulation of folliculogenesis and steroidogenesis in women by graded menotrophin administration. Hum. Reprod. 17, 2009 – 2015 Filicori, M. et al. Comparison of controlled ovarian stimulation with human menopausal gonadotropin and recombinant follicle stimulating hormone. Fertil. Steril. (in press) Strehler, E. et al. (2001) Impact of recombinant follicle-stimulating hormone and human menopausal gonadotropins on in vitro fertilization outcome. Fertil. Steril. 75, 332 – 336 Martin, L. et al. (2002) Daily low dose recombinant hCG and recombinant FSH: a novel stimulation protocol for IVF. Fertil. Steril. 76, S19 Filicori, M. and Cognigni, G.E. (2001) Clinical review 126: roles and novel regimens of luteinizing hormone and follicle-stimulating hormone in ovulation induction. J. Clin. Endocrinol. Metab. 86, 1437– 1441
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Current concepts and novel applications of LH activity in ovarian stimulation Marco Filicori, Graciela E. Cognigni, Patrizia Pocognoli, Walter Ciampaglia and Silvia Bernardi Reproductive Endocrinology Center, University of Bologna, Via Massarenti 13, 40138 Bologna, Italy
Luteinizing hormone (LH) is a crucial physiological regulator of the human menstrual cycle. LH activity is also contained in many medications used to treat anovulation and to stimulate multiple folliculogenesis for assisted reproduction techniques. However, LH activity had previously been regarded as just a contaminant of follicle-stimulating hormone (FSH)-containing products and deemed potentially detrimental for reproductive function. Novel experimental and clinical evidence now suggests that the administration of pharmacological amounts of LH activity, instead of being harmful, is therapeutically advantageous, particularly in the support and modulation of ovarian folliculogenesis. The aim of this article is to provide an overview of the effects of LH activity administration in ovarian stimulation and to outline novel unconventional gonadotropin regimens that might improve the efficacy, safety and convenience of ovulation induction. Medications that restore or therapeutically modify the ovulatory process have been used for over four decades in the management of menstrual cycle disorders and for the treatment of infertility. Ovulation induction can be applied to treat anovulation or to stimulate multiple folliculogenesis in patients who are candidates for assisted reproduction technology (ART), a procedure also termed controlled ovarian stimulation (COS). Complications can occur during exogenous gonadotropin administration, including multiple gestations and the ovarian hyperstimulation syndrome (OHSS). With some notable exceptions, such as the use of gonadotropin-releasing hormone (GnRH) analogs, gonadotropin administration regimens have not greatly changed since the 1960s, and still rely on the capacity of these medications to overcome and disrupt the normal hormonal control mechanisms of the spontaneous menstrual cycle to force the ovary to produce one or more reproductively competent follicles and oocytes. The use of novel therapeutic regimens that more closely mimic the hormonal dynamics of the spontaneous menstrual cycle might enable us to improve this form of therapy through a greater control of folliculogenesis. Corresponding author: M. Filicori ([email protected]).
Gonadotropin actions on ovarian follicles Theca cells Luteinizing hormone (LH) stimulates theca cell (TC) androgen production; LH receptors are present on TCs from fetal life (Table 1). TC androgens are transferred into granulosa cells (GCs) and turned into estrogens through the catalytic action of the aromatase system; folliclestimulating hormone (FSH) alone induces the aromatase system in small antral follicular GCs. This modular action of gonadotropins was named the ‘two cell-two gonadotropin model’ [1]. GC-produced estrogens play a fundamental role in the reproductive system by improving follicle and oocyte maturity, priming the hypothalamic – pituitary unit and inducing the morphological uterine and endometrial changes needed for embryo implantation. Granulosa cells The capacity of LH to interact with ovarian GCs is dependent upon the development of specific LH receptors by these cells (Table 1). During the follicular phase, FSH stimulates GCs to express LH receptors [2]; this action is facilitated by estrogens. Thus, in the late stages of follicle development, GCs become responsive to LH, which can exert virtually all of the physiological actions of FSH on GCs, including the stimulation of the aromatase system [3]. Because of these events, the two cell-two gonadotropin model is not fully applicable throughout the entire lifespan of the ovarian follicle and must be revised and reassessed at least for the late part of GC functional life [4]. The rise in serum FSH levels typical of the luteal – follicular transition is crucial for stimulating ovarian follicle recruitment. Conversely, the reduced FSH levels in Table 1. The occurrence of FSH and LH receptors in the theca and granulosa cells of the human ovary at different stagesa Stage of life
Theca cell receptors FSH
LH
Granulosa cell receptors FSH LH
Prenatal Prepubertal Adult menstrual cycle Early follicular Mid- to late-follicular
2 2
þ þ
þ þ
2 2
2 2
þ þ
þ þ
2 þ
a
Abbreviations: FSH, follicular stimulating hormone; LH, luteinizing hormone.
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the remaining part of the follicular phase prevent the further emergence of immature follicles, whereas progressively increasing LH levels support the growth and maturation of the dominant follicle. Almost two decades ago it was suggested that FSH stimulation might not be required once GCs express adequate amounts of LH receptors [3]; this concept was recently tested and confirmed in humans [5– 7]. The expression of GC LH receptors enables the larger follicle(s) to keep growing and to develop dominance over smaller follicles, the GCs of which are devoid of LH receptors [8]. This dynamic interplay of serum gonadotropin secretion and receptor expression by different ovarian cells enables the uninterrupted progression of folliculogenesis to occur from a large pool of immature follicles, until ovulation of a single dominant follicle. These changes in receptor expression are also the basis for the mechanism of action of gonadotropin administration during ovulation induction. Use of LH activity to treat anovulation Gonadotropin medications used for ovulation induction and COS are listed in Table 2. Traditional human menopausal gonadotropin (hMG) contains 75 IU of FSH combined with 75 IU of LH activity or less. A new highly purified (HP) formulation of hMG that can be administered subcutaneously is now also available [9]. Human chorionic gonadotropin (hCG) also contributes to the LH activity of menotropins [10]. Limited published data exist on the specific effects of the administration of different forms of LH activity; however, hCG potency appears to be approximately six times greater than that of LH [11]. Gonadotropin preparations devoid or with highly reduced LH activity include human FSH (hFSH), HP FSH, and recombinant FSH (rFSHa and rFSHb), whereas only LH activity is contained in recombinant LH (rLH), hCG and recombinant chorionic gonadotropin (rCG). Treatment of hypogonadotropic hypogonadism Reduced gonadotropin levels in hypogonadotropic hypogonadism (HH) are mostly related to a deficit of GnRH
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secretion. Although HH patients tend to respond well to gonadotropins, combined FSH and LH activity administration appears to be necessary in this condition [12]. FSHonly administration requires greater gonadotropin doses and results in fewer preovulatory follicles, lower estradiol (E2) levels, and reduced endometrial thickness and incidence of ovulation [13 – 15]. Oocyte quality might also be affected by LH activity deprivation because reduced oocyte fertilization occurred after HP FSH treatment [16]. Serum estrogen levels and folliculogenesis were positively correlated with the amount of rLH administered during rFSH administration [17]. Low-dose hCG or rCG can also be used to supply LH activity to HH patients; controlled ovarian stimulation was shortened and the HP FSH dose was reduced after the addition of 50 IU d21 of hCG [18]. A combined regimen of rFSH (75 IU d21) and rCG (2.5 mg d21) in one HH patient resulted in E2 increments, the development of a dominant follicle and pregnancy [19]. Thus, LH activity supplementation in HH patients improves gonadal steroid biosynthesis, follicle development, endometrial thickness, treatment parameters (duration and gonadotropin dose) and overall therapeutic success of ovulation induction. Treatment of polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is often associated with high endogenous LH secretion, menstrual cycle disorders, infertility and high rates of spontaneous abortion. Excessive LH levels stimulate theca cell androgen secretion and could be involved in small follicle atresia. It was suggested that LH might directly or indirectly hasten late follicular phase meiotic maturation through disruptions of GC communication in the cumulus oophorus [20]. Nevertheless, the success of ART is not reduced in PCOS because the number and quality of oocytes and embryos is at least as good (and often superior) to those of control subjects [21]. Furthermore, convincing evidence is being accrued to suggest a close link between the reproductive system defects of PCOS and hyperinsulinemia [22]. Metformin administration restored the response of PCOS patients to
Table 2. Types, gonadotropin content and brand names of gonadotropin preparations currently available in European countries and North Americaa,b Type of gonadotropin Human derived HP FSH hFSH hMG hMG HP hMG Recombinants rFSHa rFSHb rLH Chorionic gonadotropins hCG rCG a
Gonadotropin activity content per ampoule/vial FSH LH
Brand names
75 IU 75 IU 75 IU 75 IU 75 IU
, 0.1 IU , 1 IU 25 –35 IU 75 IU 75 IU
Metrodin HP, Bravelle Metrodin, Fostimon Normegon, Pergogreen Pergonal, Humegon, Menogon, Repronex Menopur
37.5– 1200 IU 50– 200 IU A
A A 75 IU
Gonal F Puregon, Follistim Luveris
A A
CG 250 –5000 IU CG 250 mg
Profasi, Gonasi, Novarel, Choragon, Pregnyl Ovidrel
Abbreviations: A, absent; CG, chorionic gonadotropin; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; hFSH, human follicle-stimulating hormone; hMG, human menopausal gonadotropin; HP FSH, highly purified follicle-stimulating hormone; HP hMG, highly purified human menopausal gonadotropin; LH, luteinizing hormone; rCG, recombinant chorionic gonadotropin; rFSHa, recombinant follicle-stimulating hormone a; rFSHb, recombinant follicle-stimulating hormone b; rLH, recombinant luteinizing hormone. b Drug formulations and brand names might differ in some countries. http://tem.trends.com
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clomiphene citrate [23], and normalized estrogen levels and follicle response during gonadotropin administration, possibly through a reduction of GC aromatase activity [24], and was associated with dramatic improvements in the occurrence of spontaneous and recurrent abortion [25,26]. Although additional evidence obtained through randomized controlled trials will be needed before metformin is applied routinely [27], hyperinsulinemia rather than increased LH secretion per se appears to be the key factor in the pathogenesis of reproductive system dysfunctions in PCOS. Early investigations showed no difference [28] in ovulatory and pregnancy rates between hMG and hFSH [29]; the number of follicles and the occurrence of ovarian hyperstimulation were actually greater after hFSH. Twelve PCOS patients were assessed by Larsen et al. [30] in a randomized, double blind, crossover study that compared hFSH and hMG; no significant treatmentrelated differences were found in the variables assessed. A larger study comprising 30 PCOS patients also failed to detect an advantage in the use of hFSH versus hMG administered in a low-dose regimen [31]. A lack of improvements in pregnancy rates of FSH-only administration over hMG in PCOS ovulation induction was recently confirmed by two Cochrane meta-analyses of randomized controlled trials [32,33]. Thus, LH activity administration through hMG does not appear to be detrimental to ovulation induction in PCOS. Use of LH activity in assisted reproduction Larger amounts of exogenous gonadotropins are used to achieve the high oocyte recovery yields needed for ART procedures. Although most of the gonadotropin preparations listed in Table 2 are used in clinical practice, no agreement exists regarding exact treatment regimens and protocols. One heated debate regards the possibility that LH activity-containing preparations might provide better and more efficient results than the administration of FSH-only products; however, few studies have systematically addressed this issue. Retrospective meta-analyses comparing LH-containing regimens with LH-free stimulation regimens have provided conflicting results [34– 36]. Is there a threshold and ceiling for LH activity? It has been suggested that a ‘threshold’ and a ‘ceiling’ might exist in LH activity, (i.e. an optimal range for LH action), and that excessive LH activity administration might negatively affect treatment outcome in ovulation induction and ART [37]. The presence of low baseline LH concentrations is associated with HH or the suppressive action of GnRH agonists in otherwise normal patients. Women with low endogenous LH secretion respond better to ovulation induction when both FSH and LH activity are administered [38,39]. Furthermore, patients with intermediate levels of residual endogenous LH secretion on stimulation day 8 were found to respond optimally, whereas women with higher or lower LH concentrations had reduced success rates in ART [40]. Although it was suggested that patients with less profound suppression of endogenous gonadotropins might not benefit from LH supplementation, these negative findings might be related http://tem.trends.com
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to the modest amounts of LH activity administered (rLH, 25–150 IU d21) [41,42]. Recent studies also suggested that the administration of even small amounts of LH activity could be detrimental to embryo quality and implantation in some patients [40,43]. These findings conflict with other studies that failed to demonstrate such negative effects of LH [44], and other investigations that actually suggested a positive action of LH activity on implantation [45] and miscarriage prevention [38,46]. The use of 150 IU d21 of LH activity given as HP hMG did not cause untoward effects in ART [47], and in our experience even the administration of much larger amounts of LH activity (e.g. hCG 200 IU d21, corresponding to 1,200 IU d21 of LH) did not hamper the reproductive potential of ART patients [7]. The apparent contradiction of these studies might be related to a selection bias in the patients who ended up responding worse to LH activity administration. Thus, it appears that, although LH activity should always be administered in conditions of profound endogenous LH suppression (the threshold concept), evidence in support of the existence of a ceiling of LH activity is controversial, at least within the drug regimens currently used in ART [48]. Oocyte/embryo quality and follicular environment Disagreement exists regarding oocyte and embryo quality obtained with different gonadotropin regimens. Early studies [49] found a higher percentage of mature oocytes in patients treated with human-derived FSH than in patients receiving hMG or a combination of these gonadotropins [50]. Conversely, more recent reports provided conflicting results [42], or could not identify a significant difference in metaphase II oocytes between treatment with hMG and with human-derived FSH [51] or rFSH [44,52]; embryo quality was also comparable [44]. Furthermore, implantation rates were found to be positively correlated with the LH activity dose administered [45], and LH activity dramatically improved implantation and pregnancy rates following blastocyst transfer [46]. Higher follicular fluid content of LH at the time of oocyte retrieval was associated with improved embryo quality [53,54]. Even in PCOS patients (who have high endogenous LH secretion), mature oocyte yield and cleavage rates were similar in hMG and hFSH-treated patients [55] and no significant differences in ART outcome (oocyte maturity and fertilization rates) were found when rFSH and hMG were compared [56]. Premature luteinization Although serum progesterone (P) levels are usually low during gonadotropin administration in ART patients, moderate serum P increments (usually 1 – 3 ng/ml) can occasionally be seen during COS [57,58] and were thought to be caused by GC luteinization of developing follicles induced by premature LH increments or the hCG content of hMG [59]. These small P increments are not detrimental to oocyte or embryo quality [60 – 63], but it was suggested that they might reduce ART success through secretory endometrial transformations that hamper embryo implantation [64]. Profound endogenous LH suppression with GnRH agonists [63,65] or GnRH antagonists [66], and the use of FSH-only preparations [63] failed to eliminate
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Fig. 1. Correlation between serum progesterone (P) levels during ovulation induction and the total amounts of (a) follicle-stimulating hormone (FSH) activity and (b) luteinizing hormone (LH) activity administered to each patient. P levels were determined daily throughout gonadotropin administration in each patient and expressed as area under the curve. Reproduced, with permission, from [69].
premature luteinization. Furthermore, hMG administration [67] or FSH supplementation with 50 IU d21 of hCG [68] did not significantly affect serum P levels. In a recent larger study [69], the LH activity dose administered was found to be unrelated to serum P levels; conversely, a positive and highly significant correlation was found between the FSH dose administered and serum P levels (Fig. 1). Finally, even larger amounts of LH activity did not greatly affect P secretion [6,7]. This information points towards FSH, rather than LH and hCG, as the causative agent of P increments during COS [63]. Such an interpretation was supported by our recent finding that rFSH (a more active stimulator of GC function than human-derived FSH) was associated with higher P concentrations during COS [47]. Thus, the term ‘premature luteinization’ appears to be a misnomer because moderate follicular phase P increments seem to reflect greater FSH-induced GC steroidogenetic activity; this phenomenon might be reduced by lowering the amount of FSH used in ovulation induction. Because LH activity co-administration permits the curtailment of
Preovulatory follicles <10mm
(a)
the FSH dose used in COS [40,67,68], LH activity-rich regimens could limit rather than cause ‘premature luteinization’. Modulation of folliculogenesis The degree and quality of folliculogenesis achieved through COS appears to be affected by different gonadotropin preparations. Following FSH priming, LH activity can support and stimulate the growth of large antral follicles [6,7] through its interaction with GC LH receptors. Conversely, hMG administration leads to a progressive decline in the number of small (, 10 mm) ovarian follicles [67]. FSH alone enhances, whereas LH decreases, the number of small (, 10 mm) preovulatory follicles (Fig. 2) [69]; this effect can be brought about by very small amounts of LH activity (e.g. 37.5 IU d21) [6]. Although this reduction in small preovulatory follicles could also be the result of the lower FSH doses administered, the finding that this phenomenon also occurs when FSH is maintained at a constant level suggests a specific LH-related effect [6]. (b)
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r = 0.193 P <0.05
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Fig. 2. Correlation between the number of small preovulatory follicles (, 10 mm diameter) and the total amounts of (a) follicle-stimulating hormone (FSH) and (b) luteinizing hormone (LH) activity administered to each patient. Reproduced, with permission, from [69]. http://tem.trends.com
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Novel LH activity administration regimens Recent findings suggest that LH activity administration can be extremely effective in the late stages of ovulation induction and COS, and can support ovarian follicle development even in the absence of FSH administration. Sullivan et al. [5] found that replacement of rFSH with rLH (150 or 375 IU, twice daily) at the end of COS prevented the E2 decline associated with rFSH discontinuation. After one week of ovarian priming with rFSH, we treated GnRH agonist-suppressed patients with various combinations of rFSH and low-dose hCG; most patients completed treatment with comparable numbers of large preovulatory follicles and serum E2 levels, even when exogenous FSH was completely discontinued [6]. Finally, when an eight-day course of hMG was followed by five days of low-dose hCG alone, E2 levels and the growth of large ovarian follicles continued to increase (Fig. 3); several mature oocytes were retrieved and pregnancy was achieved with intracytoplasmic sperm injection [7]. We suggested that these features could be applied to COS by providing an FSH prevalent stimulation in the early stages of treatment to enhance follicle recruitment, followed by an LH prevalent stimulation to support selectively the development of larger and reproductively competent follicles [48,73]; in addition to reducing FSHrelated costs, these regimens might provide a means of achieving better and safer COS by increasing follicular fluid estrogen concentrations (and hence oocyte quality), and reducing the occurrence of small preovulatory follicles that might predispose patients to the development of OHSS.
hMG 225 IU day–1
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FSH-only versus combined FSH and LH activity administration Patients treated with hMG have higher serum LH, hCG and E2 levels and fewer small (, 10 mm diameter) preovulatory ovarian follicles than patients receiving HP FSH or rFSH [67,70]. Furthermore, we recently found that serum immunoreactive FSH levels are significantly increased after hMG and HP hMG administration versus rFSH [47,70]; this feature is probably related to the different FSH isoforms found in human-derived and recombinant products. Oocyte and embryo quality, pregnancy rates and pregnancy outcome did not differ when rFSH was compared with hMG [71] or HP hMG [9]; this finding was confirmed by a recent meta-analysis [35]. Pregnancy rates and ovulation induction complications were similar when rFSHa was compared with hMG [70] or HP hMG [47]; however, treatment duration and the gonadotropin dose used were significantly increased in patients treated with rFSHa in both studies. Supplementation of HP FSH 150 IU d21 with 50 IU d21 of hCG hastened large follicle development and reduced treatment duration and the HP FSH dose needed to achieve comparable folliculogenesis and serum E2 levels [68]. Co-administration of rFSH and rCG (2.5 mg d21, roughly corresponding to 300 IU d21 of LH) in subjects undergoing COS for oocyte donation resulted in higher preovulatory E2 levels and a significantly greater number of oocytes and embryos available for cryopreservation [72].
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Fig. 3. Daily serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG), estradiol (E2), progesterone (P) and testosterone (T) and the number of large ((a) .14 mm diameter], intermediate [(b) 10 –14 mm] and small [(c) ,10 mm] ovarian follicles detected at transvaginal pelvic ultrasound during ovulation induction in a patient undergoing intracytoplasmic sperm injection. human menopausal gonadotropin (hMG) was administered at a dose of 225 IU d21 until treatment day 7 and then discontinued; thereafter, hCG (200 IU d21) was given alone to support follicular growth for five days. On the last ultrasound, 15 large, one intermediate and two small follicles were detected. This patient conceived and carried to term a twin pregnancy. Reproduced, with permission, from [7].
Conclusions Ovarian induction remains a key therapeutic step in the management of infertile couples. Current ovarian stimulation techniques are almost completely focused on FSH and tend to disregard the key role played by LH in menstrual cycle physiology; the non-detrimental or frankly positive outcome of LH activity administration in several published studies suggests that the use of LH activity should be expanded. LH stimulation shortens FSH treatment, reduces FSH dose requirements, does not cause premature follicle luteinization and improves the last ovarian stimulation stages by limiting the development of small antral follicles. Nevertheless, it is also evident that
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this field remains controversial and that additional studies and randomized controlled trials should be carried out to clarify and define the clinical benefits and possible drawbacks of LH activity administration during COS. The most challenging concept in this area is related to the demonstration that the development of the more mature ovarian follicles can be stimulated by the sole administration of LH activity. Much remains to be done to devise clinically suitable gonadotropin regimens based on this principle; randomized controlled trials that assess the merits of these treatment Scheme in ART are not yet available. Nevertheless, once therapeutic efficacy is confirmed, this approach might enable us to reduce the costs and complications of infertility treatment.
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Acknowledgements We thank Nadia Torcoletti for preparation of the manuscript. M.F. is a scientific advisor to Ferring Pharmaceuticals.
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