Marco Filicori

The role of luteinizing hormone in folliculogenesis and ovulation induction

OBJECTIVEnTo review the physiologic, pathophysiologic, and clinical roles of LH in follicle and oocyte development and maturation and to assess the effects of LH content in exogenous gonadotropin preparations used for ovulation induction.nnnDESIGNnCritical review of the scientific literature devoted to folliculogenesis. Evaluation of comparison studies that used different gonadotropin preparations for ovulation induction.nnnCONCLUSION(S)nFolliculogenesis and oocyte maturation are complex processes that require the action of both LH and FSH. Luteinizing hormone is essential to provide the androgen substrate for estrogen synthesis, which in turn contributes to oocyte maturation and may play a relevant role in optimizing fertilization and embryo quality. Although the excessive LH secretion that is present in some disorders is detrimental to reproductive function, this is not applicable to ovulation induction with hMG because this menotropin does not increase daily plasma LH levels. The results of ovulation induction with hMG or FSH-only regimens did not differ in studies conducted in patients with polycystic ovary syndrome and in most studies conducted in ovulatory women undergoing assisted reproductive techniques; conversely, hMG was clearly superior to purified FSH for the treatment of hypogonadotropic hypogonadism. Miscarriage rates were not affected by the use of hMG. Thus, low but detectable LH concentrations positively influence the outcome of ovulation induction in patients with ovulatory disorders and women undergoing assisted reproductive techniques.

Efficiency of aseptic open vitrification and hermetical cryostorage of human oocytes.

The present study reports, as far as is known for the first time, the safety of UV sterilization of liquid nitrogen and hermetical cryostorage of human oocytes by comparing the efficiency of fresh and vitrified sibling oocytes of infertile patients. A prospective randomized study on sibling oocytes of 31 patients was carried out. Metaphase-II oocytes were randomized for intracytoplasmic sperm injection and the supernumerary sibling oocytes were vitrified using a novel Cryotop aseptic procedure (UV liquid nitrogen sterilization and hermetical cryostorage). After unsuccessful attempts with fresh oocytes, vitrified sibling oocytes were injected. Mean outcome measures observed were fertilization, cleavage and top-quality embryo rates. No significant differences were observed between the fresh and vitrified-warmed sibling oocytes: oocyte fertilization was 88.3% versus 84.9%; cleavage 72.6% versus 71.0%; top-quality embryos 33.8% versus 26.3% and mean number of transferred embryos 2.6 ± 0.1 versus 2.5 ± 0.1, respectively. Clinical pregnancy rate per cycle with vitrified-warmed oocytes was 35.5% (implantation rate 17.1%) and seven healthy babies were born. This study demonstrated that UV liquid nitrogen sterilization and hermetical cryostorage does not adversely affect the developmental competence of vitrified oocytes, allowing safe aseptic open vitrification applicable under strict directives on tissue manipulation.

GnRH Agonists and Antagonists

SummaryGonadotrophin-releasing hormone (GnRH) analogues offer a novel approach for the non-steroidal manipulation of the reproductive endocrine axis. GnRH agonists are now effectively employed in the management of precocious puberty, prostate and breast cancer, endometriosis, uterine leiomyoma, polycystic ovarian disease, and various other disorders. Unfortunately, contraceptive applications of GnRH agonists have been disappointing. The availability of slow release depot formulations of GnRH agonists, and the development of GnRH antagonists may further optimise and extend the clinical application of these compounds.

Freezing within 2 h from oocyte retrieval increases the efficiency of human oocyte cryopreservation when using a slow freezing/rapid thawing protocol with high sucrose concentration

BACKGROUNDnA number of factors influence the success of oocyte cryopreservation and subsequent ICSI. The aim of the present study is to establish the ideal time, after oocyte retrieval, for human oocyte cryopreservation via slow freezing/rapid thawing protocol with 0.3 M sucrose concentration in cryoprotectant solution (SF/RT 0.3 M).nnnMETHODSnRetrospective study with 75 patients on the clinical outcome of 93 oocyte thawing cycles divided into three groups. Group A: freezing within 2 h from oocyte retrieval. Group B: freezing between 2 and 3 h from retrieval. Group C: freezing after 3 h.nnnRESULTSnThe rate of best quality embryos was significantly higher (35.2%; P = 0.050) in Group A than in Group C (14.1%). Pregnancy and implantation rates were 39.1% (9/23) and 18.5% (10/54) in Group A. Nine clinical pregnancies per 124 thawed (7.3%) and 73 injected (12.3%) oocytes were observed in Group A versus 3 pregnancies per 174 thawed, 103 injected (1.7%, 2.9%, P = 0.046 and 0.0049) in Group B and 4 per 139 thawed, 88 injected (2.9%, 4.5%, NS) in Group C. The overall yield from oocytes cryopreserved within 2 h of retrieval was 8.1 implantations per 100 oocytes thawed.nnnCONCLUSIONSnEmbryo quality and clinical outcome of thawing cycles were significantly improved when oocyte cryopreservation by SF/RT 0.3 M was carried out within 2 h from oocyte retrieval.

Low-dose human chorionic gonadotropin therapy can improve sensitivity to exogenous follicle-stimulating hormone in patients with secondary amenorrhea

OBJECTIVEnTo assess the effect of supplementing an ovulation induction regimen of highly purified FSH with LH activity in the form of low-dose hCG therapy.nnnDESIGNnCase report.nnnSETTINGnThe Reproductive Endocrinology Center at the University of Bologna, Bologna, Italy.nnnPATIENT(S)nA woman with weight-related secondary hypogonadotropic amenorrhea.nnnINTERVENTION(S)nThe patient was treated first with highly purified FSH alone and then received highly purified FSH in combination with low-dose hCG therapy (50 IU/d).nnnMAIN OUTCOME MEASURE(S)nPelvic ultrasound examinations, serum E2 levels, duration of treatment, total dose of highly purified FSH, and outcome of treatment.nnnRESULT(S)nThe concomitant administration of low-dose hCG and highly purified FSH markedly reduced the duration of treatment and the dose of highly purified FSH, and resulted in a quadruplet pregnancy in a patient in whom several previous ovulation induction procedures had been unsuccessful.nnnCONCLUSION(S)nSupplementation of an ovulation induction regimen with an agent that has LH activity can enhance FSH-induced folliculogenesis and markedly reduce costs in women with hypogonadotropic hypogonadism. However, this increased response can be associated with complications such as multiple gestation.

Comparison of controlled ovarian stimulation with human menopausal gonadotropin or recombinant follicle-stimulating hormone

OBJECTIVEnTo carefully examine the features of controlled ovarian stimulation performed with recombinant FSH-alpha or hMG.nnnDESIGNnControlled, prospective, randomized comparison of fixed gonadotropin regimens.nnnSETTINGnAcademic research institution.nnnPATIENT(S)nFifty infertile patients who were candidates for IUI.nnnINTERVENTION(S)nPatients were randomized to receive a fixed regimen of recombinant FSH-alpha (150 IU/day, 25 patients) or hMG (150 IU/day, 25 patients), after GnRH-agonist suppression (long regimen).nnnMAIN OUTCOME MEASURESnDaily measurements of serum LH, immunoreactive FSH, hCG, E(2), P, and T. Transvaginal pelvic ultrasound every 2 days. Pregnancy and abortion rates. Cost of medications. Two recombinant FSH-alpha-treated patients did not respond. Despite matched daily FSH dose, duration of treatment (hMG 10.8 +/- 0.4 vs. recombinant FSH-alpha 12.4 +/- 0.5 days), gonadotropin dose (21.7 +/- 0.8 vs. 25.3 +/- 1.3 ampoules), gonadotropin cost (288 +/- 10 vs. 1,299 +/- 66 /cycle), serum P levels, and small preovulatory follicle number were significantly lower, and LH, hCG, immunoreactive FSH levels, and larger follicles on day 8 were significantly higher in hMG-treated patients. The pregnancy, abortion, and twin pregnancy rates did not differ.nnnCONCLUSIONnThe hMG administration was associated with: [1]. increased serum LH activity and immunoreactive FSH levels during treatment; [2]. reduced signs of premature luteinization; [3]. differential modulation of folliculogenesis; [4]. lower treatment duration, gonadotropin dose, and cost; and [5]. clinical outcome comparable to recombinant FSH-alpha.

Gonadotrophin-Releasing Hormone Agonists: A Guide to Use and Selection

SummaryThe development of superactive analogues of gonadatrophin-releasing hormone (GnRH) represents one of the most important new pharmaceutical contributions of the last 2 decades. This class of drugs is now available worldwide and is successfully employed in the management of precocious puberty, ovulation induction, prostatic cancer, premenopausal breast cancer, endometriosis, uterine leiomyoma, and for the preparation of female patients undergoing laparotomic, vaginal or endoscopic surgery. GnRH agonists are also applied with some success in other clinical conditions such as catamenial disorders, hyperandrogenism and menometrorrhagia. Studies are under way to identify other potential clinical applications such as other forms of cancer.

Different gonadotropin and leuprorelin ovulation induction regimens markedly affect follicular fluid hormone levels and folliculogenesis

OBJECTIVESnTo clarify the endocrine mechanisms underlying the outcome of different ovulation induction regimens with gonadotropins and GnRH agonists (GnRH-a).nnnDESIGNnProspective study.nnnSETTINGnReproductive Endocrinology Center, University of Bologna.nnnPATIENTSnForty eumenorrheic women randomly assigned to four groups of 10 subjects each.nnnINTERVENTIONSnOvulation induction regimens: group A, purified FSH only; group B, purified FSH and flare-up GnRH-a; group C, purified FSH and long GnRH-a; and group D, hMG and long GnRH-a.nnnMAIN OUTCOME MEASURESnPelvic ultrasound and hormone levels in daily serum samples and in follicular fluid drawn immediately before hCG administration.nnnRESULTSnExogenous gonadotropin dose did not differ among groups. Group B had fewer preovulatory follicles than group C. Group B had higher serum LH, FSH, E2, P, T, and follicular fluid LH, E2, T, and alpha-inhibin than groups C and/or D. Groups C and D did not differ.nnnCONCLUSIONSnLong GnRH-a regimens improved follicle yield and the endocrine milieu in spite of comparable exogenous gonadotropin dose and lower serum FSH and thus appear to be preferable in assisted reproduction. Reduced folliculogenesis found in flare-up GnRH-a regimens could be mediated by the atretic effects of high intraovarian androgens. Efficacy of purified FSH and hMG was comparable.

Current concepts and novel applications of LH activity in ovarian stimulation

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.

Intracytoplasmic sperm injection pregnancy after low-dose human chorionic gonadotropin alone to support ovarian folliculogenesis

OBJECTIVEnTo prove that several days of low-dose hCG alone can be used to stimulate folliculogenesis, complete FSH-initiated follicle/oocyte maturation, and achieve pregnancy in assisted reproduction technology.nnnDESIGNnCase report.nnnSETTINGnReproductive endocrinology center at an academic institution.nnnPATIENT(S)nA 35-year-old female patient and her partner with male-related infertility.nnnINTERVENTION(S)nAfter an 8-day priming with hMG (225 IU/d), we administered low-dose hCG (200 IU/d) alone for 5 days in one GnRH-agonist suppressed patient until proper follicle development was obtained and intracytoplasmic sperm injection was performed.nnnMAIN OUTCOME MEASURE(S)nDaily serum levels of LH, FSH, hCG, E(2), P, and T; measurements of follicle number and size; oocytes retrieved and fertilized; pregnancy.nnnRESULT(S)nAlthough FSH levels rapidly declined after hMG discontinuation, E(2) and large follicles increased during hCG-only administration. Several good quality oocytes were retrieved and fertilized by intracytoplasmic sperm injection; three embryos were transferred and a twin pregnancy ensued.nnnCONCLUSION(S)nReplacement of FSH with low-dose hCG for several days in the late ovulation induction stages of assisted reproduction technology resulted in: [1] continued growth of large ovarian follicles and E(2); [2] an optimal preovulatory follicle pattern consisting of many large and few medium and small follicles; and [3] reproductively competent oocytes and pregnancy.