Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis

Around 400 follicles sequentially mature and ovulate duringan average women‘s reproductive lifetime. From birth tothe menopause, the other 99.98% of her follicles begin developmentbut never complete it. Instead they default to atresia due toinadequate stimulation by follicle stimulating hormone (FSH).Follicular growth to the stage of antrum formation (0.25 mmdiameter) is independent of gonadotrophic stimulation. Antrumformation and further growth to the stage at which folliclesbecome potentially able to begin pre-ovulatory development (2–5mm diameter) require tonic stimulation by FSH. Before onsetof puberty, blood concentrations of FSH do not rise sufficientlyto sustain development beyond this stage, therefore all antralfollicles become atretic. After puberty, as each menstrual cyclebegins, FSH concentrations rise beyond a critical ‘threshold’and multiple follicles are recruited to begin pre-ovulatorydevelopment. Due to increases in its responsiveness to FSH andluteinizing hormone (LH), one of these follicles becomes selectedto ovulate while the remainder become atretic. At mid-follicularphase, the dominant follicle reaches 10 mm in diameter and increasinglysynthesizes oestradiol. Tonic stimulation by FSH and LH, underpinnedby local paracrine signalling, maintains oestrogen secretionby the dominant follicle, which grows to 20 mm in diameter beforeit ovulates in response to the mid-cycle LH surge. The development-relatedresponse to LH shown by the pre-ovulatory follicle raises thepossibility that exogenous LH might be used as an adjunct totherapy with exogenous FSH in clinical ovulation induction regimenswhere the aim is to induce monovulation.     

Successful induction of ovulation and completed pregnancy using recombinant human luteinizing hormone and follicle stimulating hormone in a woman with Kallmann's syndrome

The induction of ovulation in women with hypogonado-trophichypogonadism requires follicle stimulating hormone (FSH) forfollicular growth and both FSH and luteinizing hormone (LH)to induce optimal follicular steroidogenesis. The developmentof human recombinant FSH and LH means that individually tailoreddoses of both hormones can be used with the aim of inducingunifollicular ovulation. This report describes the use of recombinanthuman FSH and LH for the induction of ovulation and conceptionin the second cycle of treatment, and subsequently a successfullycompleted pregnancy in a woman with Kallmann's syndrome.     

Endocrinology: Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophin-releasing hormone antagonist-treated monkeys

Both follicle stimulating hormone (FSH) and luteinizing hormone(LH) are proposed requirements for follicular growth and steroidogenesis;however, the role of LH in primate folliculogenesis is unclear.Follicular stimulation by recombinant human FSH (n = 5) withand without recombinant LH (1: 1; n = 6) following 90 days ofgonadotrophin-releasing hormone (GnRH) antagonist (Antide) treatmentin macaques was evaluated. Human chorionic gonadotrophin (HCG)was administered when six follicles >4 mm were observed.Oocytes were aspirated 27 h later and inseminated in vitro.Chronic Antide reduced serum oestradiol and bioactive LH toconcentrations observed in hypophysectomized rhesus monkeys.Multiple follicular growth required a longer interval followingrecombinant FSH (12 ± 1 days) than recombinant FSH +recombinant LH (9 ± 0.2 days), but the total number offollicles/animal did not differ between groups. The day priorto HCG, oestradiol concentrations were 4-fold less followingrecombinant FSH compared to recombinant FSH + recombinant LH.With recombinant FSH, more oocytes completed meiosis to metaphaseII(51%) and fertilized (89 ± 5%) relative to recombinantFSH + recombinant LH (12 and 52 ± 11% respectively).Follicular growth and maturation in LH-deficient macaques occurredwith FSH alone. Thus, LH is not required for folliculogenesisin primates. Higher fertilization rates following follicularstimulation with FSH alone suggest that the presence of LH withFSH (1: 1) during the pre-ovulatory interval impairs gametogenicevents in the periovulatory period.     

Differential FSH exposure in preantral follicle culture has marked effects on folliculogenesis and oocyte developmental competence

BACKGROUND: We investigated at what stage early cultured preantral mouse follicles become dependent on a minimal effective FSH dose (10 mIU/ml) and analysed the influence of implementing FSH at several time-points during in vitro culture. METHODS: Two-layered mouse follicles were cultured for 12 days under seven different FSH exposure regimens and ovulated on day 13 by hCG/EGF. Ovulated cumulus-oocyte complexes were fertilized and embryos were cultured up to the blastocyst stage. RESULTS: When FSH was absent or added only once at the start of culture, follicle survival was significantly reduced (22 and 52% respectively versus 95% when FSH was continuously present, P < 0.01) and oocyte quality was compromised, providing few oocytes for embryo culture (19 and 7% versus 71% in continuous presence of FSH, P < 0.01). Optimal follicle survival rates can be ensured by implementing FSH at the latest from day 4 of culture. By introducing FSH later than day 4, follicle survival rates and number of ovulated oocytes decreased. Estradiol production and luteinization were strongly related to the moment of introducing FSH in culture. Fertilization and preimplantation embryo development rate were found to be highest in cultures where FSH support was implemented during the preantral stage. CONCLUSION: Exposure to FSH before formation of the antral-like cavity had a positive effect on follicle survival and oocyte robustness.     

Endocrinology: Human chorionic gonadotrophin self-administered by the subcutaneous route to induce oocyte maturation in an in-vitro fertilization and embryo transfer programme

This study was initiated to evaluate oocyte maturation and theoutcome of in-vitro fertilization (IVF) cycles following thes.c. administration of human chorionic gonadotrophin (HCG) bythe patient herself or her partner. A group of 104 women whoentered our IVF embryo transfer programme were prospectivelyrandomized to have 5000 IU or 10 000 IU HCG s.c. or i.m. TheHCG was administered for induction of the final oocyte maturationin cycles with pituitary down-regulation with a gonadotrophin-releasinghormone agonist according to a long protocol and where ovarianstimulation had been achieved with pure follicle stimulatinghormone. The mean concentration of HCG in serum 12 and 36 hafter the HCG injection was significantly higher in the womenreceiving 5000 IU i.m. compared to the s.c. route. However,in women receiving 10 000 IU HCG there were no significant differencesin the mean concentrations 12 and 36 h after the injection,irrespective of the route of administration. Furthermore, therewere no significant differences in the relative numbers of retrievedmature oocytes between the groups. When comparing the clinicaloutcome in the different groups, no significant differenceswere found between those receiving 5000 IU or 10 000 IU HCG,i.m. or s.c. Our data indicate that HCG can be given s.c. withoutreducing the chance of retrieving a mature oocyte and that theclinical outcome with regard to pregnancies is not negativelyaffected.     

Recombinant follicle stimulating hormone in in-vitro fertilization treatment-clinical experience with follitropin alpha and follitropin beta

The objective of this prospective study was to compare the outcome of ovarian hyperstimulation for in-vitro fertilization (IVF) using two different preparations of recombinant follicle stimulating hormone (FSH). The study was based on 296 consecutive IVF cycles in 1997, 199 performed using follitropin alpha (Gonal-F) and 97 performed using follitropin beta (Puregon). Outcome was compared regarding pregnancy rate, oestradiol and progesterone response, endometrial thickness, follicle number, number of retrieved oocytes, fertilized oocytes, sperm count and sperm motility. There was no significant difference in outcome of stimulation. Clinical pregnancy rate was similar, 29.1% for Gonal-F and 28.1% for Puregon. There was no difference in endometrial response, oestradiol response, number of smaller (12-15 mm) or larger (>15 mm) follicles, number of oocytes retrieved, fertilized, divided and replaced, in sperm counts or in sperm progressive motility. There was a lower follicle number in the Puregon group, but not statistically significant. The serum progesterone concentrations on the day of oocyte retrieval, however, were significantly lower in the Puregon group. In conclusion, it was not possible to find significant differences in the IVF programme with regard to stimulation outcome between Gonal-F and Puregon. The results of this study indicate that Gonal-F and Puregon may be equally suitable for use in ovarian stimulation for IVF.     

A prospective, randomized comparison of ovulation induction using highly purified follicle-stimulating hormone alone and with recombinant human luteinizing hormone in in-vitro fertilization.

The commercial availability of highly purified, s.c. administered urinary follicle stimulating hormone (FSH) preparations for ovarian stimulation marked the beginning of a new era in the treatment of infertility. As these new formulations contain essentially no luteinizing hormone (LH), supplemental LH may be needed for optimal folliculogenesis. It was the aim of this pilot study to compare fertilization rates, embryo morphology, implantation rates and pregnancy outcomes prospectively in two age-matched patient groups: women who received highly purified FSH (FSH-HP) (n = 17), and women who received FSH-HP plus recombinant human LH (rhLH, n = 14) throughout ovarian stimulation. All patients received mid-luteal pituitary down-regulation with s.c. gonadotrophin-releasing hormone agonist (GnRHa) (leuprolide). Mean implantation rates were 26.9 and 11.9% in the FSH-HP only and FSH-HP + rhLH groups respectively. The mean clinical pregnancy/initiated cycle rate was 64.7 and 35.7% for the FSH-HP only and FSH-HP + rhLH patients respectively. FSH-HP patients and FSH-HP + rhLH patients achieved clinical pregnancy/transfer rates of 68.8 and 45.5% respectively. One patient in the FSH-HP + rhLH group had a spontaneous abortion; no pregnancy losses occurred in the FSH-HP only group. There were more cancellations for poor ovarian response among FSH-HP + rhLH patients (n = 3) than among FSH-HP patients (n = 1). The trend toward better pregnancy outcomes among patients who received FSH-HP without supplemental rhLH did not reach statistical significance. It is postulated that appropriate endogenous LH concentrations exist despite luteal GnRHa pituitary suppression, thereby obviating the need for supplemental LH administration.     

A prospective, randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle stimulating hormone (Puregon versus Metrodin) in in-vitro fertilization

Urinary follicle stimulating hormone (FSH) is being used forthe treatment of human infertility. Recently, FSH manufacturedby means of recombinant DNA technology with a much higher purity(>99%) has become available. A prospective, randomized, assessor-blind,multicentre (n = 18) study was conducted in infertile womenundergoing in-vitro fertilization comparing recombinant FSH(Org 32489, Puregon®) and urinary FSH (Metrodin®). Eligiblesubjects were randomized (recombinant versus urinary FSH = 3:2)and pretreated with buserelin for pituitary suppression. FSHwas given until three or more follicles with a diameter of atleast 17 mm were seen. After oocyte retrieval, fertilizationroutines were applied according to local procedures. No morethan three embryos were replaced. In all, 585 subjects receivedrecombinant FSH and 396 urinary FSH. Significantly more oocyteswere retrieved after recombinant FSH treatment (mean adjustedfor centre 10.84 versus 8.95, P < 0.0001). Ongoing pregnancyrates per attempt and transfer in the recombinant FSH groupwere 22.17 and 25.97% respectively, and in the urinary FSH group,18.22 and 22.02% respectively (not significant). Ongoing pregnancyrates including pregnancies resulting from frozen-thawed embryocycles were 25.7% for recombinant and 20.4% for urinary FSH(P = 0.05). Compared to urinary FSH, the total dose of FSH wassignificantly lower with recombinant FSH (2138 versus 2385 IU,P < 0.0001) in a significantly shorter treatment period (10.7versus 11.3 days, P < 0.0001). No clinically relevant differencesbetween recombinant and urinary FSH were seen with respect tosafety variables. It is concluded that recombinant FSH (Puregon)is more effective than urinary FSH in inducing multifolliculardevelopment and achieving an ongoing pregnancy.     

Significance of cumulus oophorus in in-vitro fertilization and oocyte viability and fertility

Fertilization and cleavage rates of human cumulus-intact oocytes incubated in vitro for 36-48 h with normal spermatozoa tended to be higher than those which were cumulus-denuded (73 versus 68%; 68 versus 56%, respectively); however, the difference was not significant. Nor were these differences significant when using sperm samples of various qualities (normozoospermic samples: 75 versus 70% fertilized oocytes; asthenozoospermic: 66 versus 64%; oligozoospermic: 64 versus 56%; oligoasthenozoospermic: 35 versus 33%). The beneficial effect of the human cumulus oophorus on the binding of human spermatozoa to denuded hamster oocytes and on head decondensation of human spermatozoa observed after 2 h of incubation (9.3 versus 7.0 bound spermatozoa per oocyte, P less than 0.05; 0.5 versus 0.3 decondensed sperm heads per oocyte, P less than 0.02) disappeared after 6 h. A protective effect of the cumulus oophorus on hamster oocytes preincubated in medium containing 50% human preovulatory follicular fluid was observed in the sperm penetration assay (fertilization rate of cumulus-intact: cumulus-denuded oocytes, 26 versus 13%, P less than 0.05) and confirmed using fluorescein diacetate stain (cumulus-intact oocytes: 86 versus 100% vitality, non-significant; cumulus-denuded oocytes: 64 versus 100%, P less than 0.01). These data suggest the accelerating effect of the human cumulus oophorus on fertilization in its early stages. Furthermore, the cumulus plays an important part in protecting the oocyte against adverse environmental influences.     

Empty follicle syndrome due to human errors: its occurrence in an in-vitro fertilization programme

We report five cases in which no oocytes were retrieved afterstandard ovarian stimulation for in-vitro fertilization (IVF),and in which it was found that mistakes had been made at thetime of human chorionic gonadotrophin (HCG) administration.In all five cases, oocyte retrieval was achieved after injectingHCG, when necessary, and reprogramming aspiration 24–36h later. A mean of 7 ± 3.2 MII oocytes were recoveredper patient and 3.2 ± 0.8 embryos were transferred. Threeclinical pregnancies were obtained, and four healthy infantswere born. In our programme, these were the only cases of emptyfollicle syndrome (EFS) that appeared over a total of 1118 cycles,and were all explained by human error in the administrationof HCG. Our experience shows that human error could be considereda significant factor in the aetiology of empty follicle syndrome,and that EFS may be in part avoided by taking simple preventivemeasures.     

Follicular development and early luteal function of conception and non-conceptional cycles after human in-vitro fertilization: endocrine correlates

Two-hundred patients, half of whom had on-going pregnancies,were examined in terms of follicular growth, urinary oestrogenand LH output, oocytes recovered and embryos replaced. The twogroups were identical in all parameters measured except thaturinary LH output was significantly higher (P>0.01) in non-pregnantpatients on the two days prior to HCG administration. Duringthe early to mid-luteal phase, plasma progesterone concentrationswere related to the number of follicles aspirated at oocyterecovery, but the overall pattern of secretion was similar inboth groups. It is concluded that monitoring urinary LH output,a non-invasive technique, may be of great value for assessingoocyte quality and predicting the outcome of in-vitro fertilizationand embryo replacement.     

The effect of human menopausal gonadotrophin and highly purified, urine-derived follicle stimulating hormone on the outcome of in-vitro fertilization in down-regulated normogonadotrophic women

It has been suggested that the luteinizing hormone (LH) activityof human menopausal gonadotrophin (HMG) preparations used forovarian stimulation in in-vitro fertilization (IVF) may haveadverse effects on reproductive outcome. In the present prospective,randomized trial of 218 infertile couples this notion was investigated.A total of 114 women were treated with Pergonal (HMG group)and 104 with Fertinorm HP (HP-FSH group). The two groups werecomparable with regard to duration of infertility, cause ofinfertility, age and number of previous IVF attempts and allhad normal basal gonadotrophin concentrations before treatmentwas started. A standard hormonal treatment consisting of pituitarydown-regulation with gonadotrophin-releasing hormone analogue(GnRHa) for 14 days starting on cycle day 21, followed by eitherHMG or highly purified follicle stimulating hormone (HP-FSH),three ampoules (225 IU) per day for 7 days, was used in allcases. The daily hormone dose was thereafter individualizedaccording to the ovarian response. A maximum of two pre-embryoswere transferred after 3 days of culture. Luteal support withprogesterone (300 mg per day intravaginally) was used in allcases. Serum concentrations of oestradiol, FSH and LH were measuredon days 1 and 8 of stimulation and on the day of oocyte retrieval.The mean number of days of stimulation, mean number of ampoulesof HMG or HP-FSH used, mean total motile sperm count on theday of oocyte retrieval and mean numbers of oocytes retrieved(13.4 versus 13.7) or pre-embryos transferred (1.8 versus 1.8)were similar for both groups. Significantly (P < 0.05) morecycles in the HP-FSH group (17 = 16%) were cancelled due tocomplete failure of fertilization than in the HMG group (7 =6%). The mean fertilization rate was significantly (P < 0.05)higher in the HMG group (56%) than in the HP-FSH group (50%),and significantly more transferable pre-embryos were obtainedin the HMG than in the HP-FSH group (mean: 4.0 versus 3.2; P< 0.01). Serum hormone concentrations were similar in thetwo groups on stimulation day 1, but differed significantlywith regard to FSH, LH and oestradiol on stimulation day 8.The clinical outcome was similar in the two groups, with anongoing pregnancy rate (>12 weeks of gestation) per startedcycle of 33% in the HMG group and 29% in the HP-FSH group. Theclinical abortion rates were similar(10 and 14%), and the implantationrate was 30% in each group. In conclusion, no detrimental effectof the LH activity of HMG on the clinical outcome of IVF inGnRHa down-regulated normogonadotrophic women was found. Tothe contrary, some beneficial effects of HMG on fertilizationrates and pre-embryo development as compared with HP-FSH weredemonstrated. These effects, as well as the differences in serumhormone concentrations during ovarian stimulation, may be causedby differences in LH content and/or in the composition of FSHisoforms of the HMG and HP-FSH preparations.     

Few instead of many: human follicle collection from follicular aspirates at oocyte retrieval

BACKGROUND: The aim of this study was to determine if follicular aspirates obtained during oocyte retrieval for IVF were a good source of ovarian follicles for research purposes. METHODS: Follicular aspirates from 86 patients were collected and examined for the presence of follicles, and histological examination of tissue sample found was undertaken. RESULTS: Follicles were only obtained from aspirates of seven out of a total of 86 patients. From these samples a total of 14 follicles was found. The follicles were primordial, primary or secondary, 40-80 microm in diameter. Three of these recovered follicles were cultured and all degenerated within 2 days. In all aspirates some groups of granulosa cells that did not contain follicles or oocytes were found, as was vaginal epithelium that was also identified and verified by histology. CONCLUSIONS: Follicular aspirates are not a useful source of human follicles. Some structures found in the aspirates may be erroneously identified as follicles.     

Endocrinology: Luteal phase oestradiol and progesterone levels are stronger predictors than follicular phase follicle stimulating hormone for the outcome of in-vitro fertilization treatment in women with tubal infertility

Basal follicle stimulating hormone (FSH) in a natural cycle,FSH on cycle days 3 and 10 in a domiphene citrate-stimulatedcycle and oestradiol and progesterone area under the curve (AUC)in the luteal phase of the ciomiphene citrate-stimulated cyclewere evaluated as hormonal predictors for the outcome of FVFtreatment in 53 normally cycling women with tubal infertility.The pregnant women had significantly fewer treatment cycles(P < 0.001) and needed fewer ampoules of gonadotrophins (P< 0.001). They also had more oocyte retrievals (P < 0.001),more oocytes per retrieval (P < 0.01), higher fertilizationrate (P < 0.001) and more replaced pre-embryos per replacement(P < 0.01) as compared with non-pregnant women. Significantdifferences were found in FSH concentrations on cycle days 3(P < 0.05) and 10 (P < 0.001) after domiphene citratestimulation and for oestradiol and progesterone AUC in the lutealphase (P < 0.001) between those women who became pregnantand those who did not become pregnant after IVF treatment Lutealoestradiol and progesterone had considerably stronger predictivevalue for the outcome of IVF treatment as compared to basalFSH and domiphene citrate challenge test.     

Progesterone supplementation in the late follicular phase of an in-vitro fertilization cycle: a 'natural' way to time oocyte recovery?

Twenty-eight patients superovulated with clomiphene citrate(CC) and human menopausal gonadotrophin (HMG) were given a singleinjection of 25 mg progesterone (P group) 4 h prior to the ovulation-indudnginjection of human chorionic gonadotrophin (HCG). Plasma andurinary LH levels were significantly higher (P < 0.05) inthe P group immediately prior to HCG compared to controls. Plasmaprogesterone concentrations were also elevated (P < 0.01)in the P group from the time of injection to oocyte recovery.The number of mature oocytes recovered was also higher (P <0.001; 59% versus 40% in controls) and the time interval betweenoocyte recovery and insemination was also shorter (P < 0.01)in the P group. The pregnancy rate/replacement 15 days afteroocyte recovery was 39% versus 23% in the P and control groupsrespectively. It was concluded that as more mature oocytes wererecovered in the P group, progesterone supplementation in thelate follicular phase may be beneficial for patients undergoingGIFT. This was borne out when the first two GIFT patients pretreatedin this way became pregnant.     

Ovarian stimulation in women undergoing in-vitro fertilization and embryo transfer using recombinant human follicle stimulating hormone (Gonal-F) in non-down-regulated cycles

In order to assess the efficacy and safety of recombinant humanfollicle stimulating hormone (FSH) in routine clinical use,ovarian stimulation with recombinant human FSH was performedin 71 patients prior to in-vitro fertilization (IVF) withoutgonadotrophin-releasing hormone (GnRH) analogues in a multicentre,non-comparative study. Human chorionic gonadotrophin (HCG) wasadministered to 58 patients (81.7%), 15 of whom underwent 19cycles with an initial dosage of three ampoules daily of recombinantFSH and 43 of whom underwent 152 cycles with four ampoules dailyfrom day 3 onwards. No significant differences were detectedbetween these two groups in all test parameters. The mean durationof treatment was 9.06 and 8.86 days respectively with a meannumber of 24.06 and 23.25 vials of recombinant human FSH administered.A mean number of 6.26 and 5.88 oocytes respectively was collected.The number of transferred embryos was 2.4 and 2.2. A clinicalpregnancy rate of 23.8% (10 out of 42) per transfer was achieved(30.9 and 20.6% respectively). Local tolerance of s.c. administrationwas excellent. Mild pain at the injection site was the dominantfinding in <20% of patients. Two cases of ovarian hyperstimulationsyndrome were noted. Recombinant human FSH is very attractiveto patients because it can be self-administered s.c. and thepreparation does not come from a human source. In conclusion,these data support the safety and efficacy of recombinant humanFSH in routine use for IVF.     

The role of oocyte donation in women who are unsuccessful with in-vitro fertilization treatment.

Oocyte donation improves the chances of becoming pregnant in some women who are unsuccessful with in-vitro fertilization (IVF) treatment. A total of 119 IVF cycles achieved a pregnancy rate per cycle of 2.5% whereas the same women, when treated with 45 cycles of oocyte donation, achieved a 24.5% pregnancy rate per cycle. To ascertain which women may be helped by oocyte donation, IVF data were analysed according to the outcome of oocyte donation. There was a difference in the number of previous natural conceptions and live births, and in the IVF fertilization rate. There was no difference in the age of the women and the numbers of oocytes collected per cycle of IVF. New criteria are therefore suggested for recommending oocyte donation to women who have previously failed to become pregnant with IVF treatment.     

Developmental potential of embryos produced by in-vitro fertilization from gonadotrophin-releasing hormone antagonist-treated macaques stimulated with recombinant human follicle stimulating hormone alone or in combination with luteinizing hormone

We previously demonstrated, in luteinizing hormone (LH)-deficientmacaques, that follicular growth and maturation occurred withadministration of exogenous (recombinant human) follicle stimulatinghormone (r-hFSH) alone, and that the oocytes recovered fertilizedat a notably higher rate than their counterparts from animalsreceiving both r-hFSH and r-hLH (Zelinski-Wooten et al., 1995).Here, the developmental potential of embryos produced from animalstreated with r-hFSH alone or in combination with r-hLH was evaluated.Embryos (n = 127) were cryopreserved, thawed and either co-culturedon buffalo rat liver cells until the hatched blastocyst stageor transferred to synchronized recipients. Although embryosfrom each treatment group demonstrated a similar ability todevelop to hatched blastocysts with a definitive inner cellmass, a significant difference was seen in cryosurvival (56versus 78%) and in developmental rate to the hatched blastocyst(12 versus 10 days) between embryos from the r-hFSH alone andthe combination group respectively. Pregnancies resulted followingoviductal embryo transfers in both groups, with corpus luteumrescue occurring on days 12–16 of the luteal phase. Insummary, r-hFSH alone during the pre-ovulatory interval is adequatefor the gametogenic events required to produce embryos thatdevelop either in vitro or in vivo; however, exposure to r-hLHmay improve embryo viability and the rate of development.     

In-vitro maturation of human oocytes from regularly menstruating women may be successful without follicle stimulating hormone priming.

This prospective randomized study investigated whether the developmental potential of in-vitro matured (IVM) human oocytes is improved by follicle stimulating hormone (FSH) priming before aspiration. Normally cycling women were recruited among couples referred for in-vitro fertilization or intracytoplasmic sperm injection because of male factor and/or tubal disease. In the first experiment, 20 women were randomly allocated to either no stimulation (n = 10) or stimulation for 3 days with rec-FSH (Gonal-F, Serono) at a fixed dose of 150 IU/day from day 3 (n = 10). The oocytes were aspirated when the follicle(s) was observed to be 10 mm and matured in vitro for 36 h. In experiment 2, 12 women received rec-FSH (150 IU/daily) from day 3. In five patients stimulation was given for 3 days and aspiration performed as in the first experiment; the remaining seven patients continued stimulation until follicles were 10 mm in diameter and aspiration was performed 72 h later. All the oocytes were cultured for 48 h. FSH priming did not increase the number of oocytes obtained per aspiration and did not improve on maturation to metaphase II, cleavage rate or embryo development. The implantation potential of IVM embryos may be improved by maturation for 36 h compared to 48 h. In the first experiment, five out of 20 patients (25%) obtained a clinical pregnancy with an implantation rate of 15% (5/33). One has delivered a healthy boy and three pregnancies are ongoing beyond 32 gestational weeks. In the second experiment, an implantation rate of 7% and a single pregnancy (8%) was obtained, with delivery of a healthy girl.     

Pure human follicle stimulating hormone has a role in the treatment of severe male infertility by assisted reproduction: Norfolk's total experience.

Fifty patients [79 in-vitro fertilization (IVF) cycles] with severe male factor infertility were included in an experimental clinical trial running from October 1987 to March 1991 to assess the potential of systemic follicle stimulating hormone (FSH) treatment to improve sperm fertilizing ability in IVF. Two groups were defined: a secondary group (24 patients, 33 IVF cycles) with a history of failed fertilization in previous IVF attempts and a primary group (26 patients, 46 IVF cycles) with poor sperm parameters which suggested that fertilization would not occur according to previously established criteria. Basic semen analysis and a battery of endocrine radioimmunoassays [serum FSH, luteinizing hormone (LH), oestradiol, prolactin and testosterone] were performed in these patients. Bioactive-FSH and LH were also determined in some patients. For this study, pure FSH was administered (150 IU i.m. three times per week) for at least 3 months, after which the semen analysis and endocrine tests were repeated. Although no significant changes were observed after FSH therapy, either in the endocrine profile or in the basic semen parameters, except for FSH radioimmunoassay levels, the fertilization rate of pre-ovulatory oocytes was significantly improved from 2 to 54.4% in the secondary group; the primary group showed a 52.3% fertilization rate. Eighteen clinical pregnancies were achieved, 11 in the primary group and seven in the secondary group, giving 30 and 26% term pregnancy rates per transfer respectively. These results, which are in complete agreement with our preliminary study, re-emphasized the benefits of systemic FSH administration as an adjunct to assisted reproduction in selected cases of severe male factor infertility.(ABSTRACT TRUNCATED AT 250 WORDS)