Uma D. Gordon, MD

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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. 


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.

Articles

The First World Congress On: Controversies in Obstetrics, Gynecology & InfertilityPrague, Czech Republic - 1999

Author | Uma D. Gordon, MD

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Gonadotropin Stimulation Regimens and Oocyte Embryo Quality