Role of Luteinizing Hormone Activity In The Stimulation of Multiple Folliculogenesis

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In the normal human menstrual cycle, the final phase of ovarian folliculogenesis leading upto the pre-ovulatory stage is gonadotropin dependent. Luteinising hormone (LH) acts synergistically with follicle stimulating hormone (FSH) to achieve follicular steroidogenesis, luteinisation and ovulation. It therefore follows that the maturational process of the oocyte contained within the follicle and its subsequent development can be influenced by the levels of LH and FSH in the circulation. With the recent availability and increasing use of FSH-only preparations the question of possible effects on oocyte development needs to be reviewed. This paper looks at the available evidence comparing FSH-only preparations to that of combined FSH and LH regimens in both the hypogonadotropic hypogonadal model as well as normogonadotropic women undergoing in vitro fertilisation (IVF).

Studies in hypogonadotropic women have shown that using FSH alone one can achieve follicular growth upto the pre-ovulatory stage. However, the presence of LH appears to increase not only the number of follicles developed but also their rate of growth, oestradiol (E2) production, and ability to luteinise and ovulate (1). A role for LH has also been demonstrated in the final stages of follicular maturation when FSH concentrations naturally decline (2). In contrast, IVF studies using purified FSH have given comparable responses to human menopausal gonadotropin (HMG) containing equal amounts of FSH and LH. This has been attributed to the presence of residual endogenous LH despite pituitary suppression. It is important to note however that in the same patients given either urinary FSH (uFSH) or HMG in subsequent cycles, better ovarian response was obtained with the latter (3). Reduced E2 production has also been reported with FSH monotherapy. While the specific biological effects of E2 over and above a certain threshold concentration may be debated, oestro gen receptors have been identified in the primate oocyte along with receptor beta expression in human granulosa cells.

Maturation of the oocyte is a complex process, and morphological parameters of assessment used in most studies are subjective. Imthurn et al. (1996) evaluated cumulus-denuded oocytes at intracytoplasmic sperm injection treatment and found a significantly higher proportion of metaphase-II oocytes with uFSH than HMG (4). Similar findings were reported in gonadotropin releasing hormone (GnRH)-antagonist and recombinant FSH (rhFSH) treated macaques indicating that oocyte nuclear maturity is independent of follicular phase LH levels. Functional maturity may however be influenced as the fertilisation potential of the oocyte appears to be compromised in a reduced LH environment. In a randomised prospective study in GnRH-analogue suppressed IVF patients, Gordon et al. (1997) compared rhFSH treatment with urinary gonadotropin preparations containing 1, 25 and 75 IU of LH per ampoule (5). A lower percentage of fertilised and a higher percentage of unfertilised oocytes were obtained with rhFSH treatment compared to the other three groups. This could be related to inhibition of the enzymes involved in steroidogenesis as seen in monkeys (6). However, supplementation with oestradiol valerate in a woman with congenital gonadotropin deficiency did not improve fertilisation implying a possible direct effect of LH (7).

A subgroup of patients have been identified on GnRH-analogue and purified uFSH treatment with profound suppression of endogenous LH resulting in reduced E2 levels in the circulation and lower overall fertilisation rates (8). Concern has also been raised about a higher incidence of failed fertilisation in IVF cycles with low LH. In their randomised trial comparing uFSH with HMG, Westergaard et al. (1996) reported significantly higher percentage of complete failure of fertilisation with uFSH (9). Gordon et al. (1997) also demonstrated a dose-related increase in the incidence of complete fertilisation failure with decreasing exogenous LH (17.6%, 13%, 11% and 0% for 0, 1, 25 and 75 IU LH respectively) (5). In contrast, Daya et al. (1995) showed a higher number of failed fertilisation cycles with hMG (10).

Embryo viability and developmental rate to the hatched blastocyst stage have been shown to be optimal in macaques in the presence of exogenous LH (11). Such a relationship has not been demonstrated in humans to date. The number of embryos available may however be lower in a LH depleted environment due to lower oocyte yields and fertilisation rates. Meta-analysis of trials comparing uFSH with HMG has shown higher pregnancy rates with FSH (12). In contrast, evaluation of the implantation potential in a randomised study showed an increasing trend with increasing LH dose (19%, 10%, 18% and 28% for 0,1,25 and 75 IU respectively) (13). While pregnancies have been reported in hypogonadal women treated with rhFSH and rhLH, to date, no pregnancies have been documented with rhFSH alone. The presence of LH at a certain concentration in the follicular phase appears to be beneficial for follicle and oocyte development. This has been unquestionably demonstrated in hypogonadotropic hypogonadism patients. Recent studies also question the need for additional LH in IVF cycles despite the presence of residual endogenous LH. Whether this is beneficial to the specific subgroup with profound LH suppression or whether there would be more universal benefit can only be demonstrated by undertaking a large randomised controlled trial. Such a study should compare rhFSH, preferably of the same make, with varying concentrations of rhLH / hCG in GnRH-analogue / antagonist suppressed IVF cycles.

References:

References

1. The European Recombinant Human LH Study Group. Recombinant human luteinising 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, 5, 1507-1514, 1998.

2. SULLIVAN MW, STEWART-AKERS A, KRASNOW JS, BERGA, SL ZELEZNIK AJ. Ovarian responses in women to recombinant follicle-stimulating hormone and luteinising hormone (LH): a role for LH in the final stages of follicular maturation. J Clin Endocrinol Metab, 84 , 1, 228-232, 1999.

3. AGRAWAL R, CONWAY GS, ENGMANN L, BEKIR JS, JACOBS HS. Implications of using follicle-stimulating hormone preparations depleted of Luteinising hormone to achieve follicular growth in vitro fertilisation. Gynaeol Endocrinol, 12 ,1, 9-15, 1998.

4. Imthurn B, Macas E, Roselli M, Keller PJ. Nuclear maturity and oocyte morphology after stimulation with highly purified follicle stimulating hormone compound and human menopausal gonadotropin. Hum Reprod. 11 ,11, 2387-2391, 1996.

5. Gordon UD, Gordon AC, Bonnar J, Harrison RF. Effect of differing doses of LH on oocyte maturation and fertilisation. Abstracts of the 13th Annual Meeting of the ESHRE, Hum Reprod, 53, 1997.

6. Zelinsky-WOOTEN MB, Hess DL, Wolf DP, Stouffer RL. Steroid reduction during ovarian stimulation impairs oocyte fertilisation, but not folliculogenesis, in rhesus monkeys. Fertil Steril, 61, 1147-1155, 1994.

7. Balasch J, Miro F, Burzaco I., Casamitjama R, Scivico S, Ballesca J.L, Puerto B, Vanrell JA. The role of luteinising hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilisation in a woman with long-standing hypogonadotropic hypogonadism and using recombinant human follicle stimulating hormone. Hum Reprod, 10, 7, 1678-1683, 1995.

8. Fleming R, Chung CC, Yates RWS, Coutts JRT. Purified urinary follicle stimulating hormone induces different hormone profiles compared with menotropins, dependent upon the route of administration and endogenous luteinising hormone activity. Hum Reprod, 11, 1854-1858, 1996.

9. Westergaard LG, Erb K, Laursen S, Rasmussen PE, Rex S. The effect of human menopausal gonadotropin and highly purified, urine-derived follicle stimulating hormone on the outcome of in vitro fertilisation in down-regulated normogonadotropic women. Hum Reprod, 11, 6, 1209-1213, 1996.

10. Daya S, Gunby J, Hughes E G, Collins JA, Sagle MA. Randomised control trial of follicle stimulating hormone versus human menopausal gonadotropin in in-vitro fertilisation. Hum Reprod, 10, 6, 1392-1396, 1995.

11. Weston AM, Zelinskiwooten MB, Hutchison JS, Stouffer RL, Wolf DP. Developmental potential of embryos produced by in vitro fertilisation from gonadotropin-releasing hormone antagonist treated macaques stimulated with recombinant human follicle stimulating hormone alone or in combination with luteinising hormone. Hum Reprod, 11, 3, 608-613, 1996.

12. Daya S. Follicle stimulating hormone versus human menopausal gonadotropin for in vitro fertilisation: results of a meta-analysis. Hum Reprod, 43, 224-229, 1995.

13. Gordon UD. Evaluation of the role of luteinising hormone in ovarian steroidogenesis and follicular maturation. MD thesis. Trinity College Dublin, 1999.