Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries

This study was designed to compare the results of treatment with, firstly, exogenous gonadotrophins, with (57 cycles) and without (65 cycles) pretreatment with a superactive analogue of luteinizing hormone releasing hormone (LHRH) and, secondly, pure follicle stimulating hormone (FSH) (50 cycles) with those of human menopausal gonadotrophin (HMG) (72 cycles) in 46 women with clomiphene-citrate-resistant anovulation associated with polycystic ovaries. Patients randomly allocated to the analogue group received buserelin (Suprefact, Hoechst, UK, Ltd, Hounslow, Middlesex), 800 micrograms/day by nasal insufflation and when hypogonadism was achieved, patients were again randomly allocated for ovarian stimulation with either FSH or HMG. Controls received FSH or HMG alone. Patients pretreated with the analogue had similar pregnancy and ovulation rates, needed larger doses and more days of gonadotrophin therapy and had more ovarian overstimulation than those receiving no pretreatment. The role of superactive LHRH analogues for induction of a single ovulation for in-vivo fertilization is thus uncertain. Pure FSH had no advantages over HMG, the LH content of HMG having no deleterious effect on the ovary.     

First established pregnancy after controlled ovarian hyperstimulation with recombinant follicle stimulating hormone and the gonadotrophin- releasing hormone antagonist ganirelix (Org 37462)

This case report describes the first established pregnancy after the use of gonadotrophin-releasing hormone (GnRH) antagonist, ganirelix (Org 37462; Organon), to prevent a premature luteinizing hormone surge during ovarian hyperstimulation with recombinant human follicle stimulating hormone (rhFSH). The pregnancy progressed normally and ended with the birth of a healthy boy and a girl after an elective Caesarean section at gestational age of 37 weeks. This case illustrates, for the first time, the use of a GnRH antagonist in combination with a pure FSH preparation for ovarian stimulation.      

Endocrinology: Pattern of gonadotrophin secretion in patients with hyperandrogenaemic amenorrhoea before and after ovarian wedge resection

The follow-up of androgen and gonadotrophin concentrations afterovarian wedge resection is reported in two patients with hyperandrogenaemicamenorrhoea. Elevated testosterone concentrations decreasedimmediately and androstenedione after 3 months. In a patientwith polycystic ovarian disease, luteinizing hormone (LH) amplitudeswere reduced in the presence of unchanged pulse frequency. Smalldecreases in mean LH baseline values were accompanied by increasesin follicle stimulating hormone concentrations. Our data provideevidence that reduction of elevated ovarian androgen concentrationsleads (directly or indirectly) to a decrease of exaggeratedLH pulse amplitude in patients with hyperandrogenaemic amenorrhoea.     

Infertility: Late low-dose pure follicle stimulating hormone for ovarian stimulation in intra-uterine insemination cycles

At present, there is general agreement that ovarian stimulationimproves pregnancy rates after intra-uterine insemination (IUI).Also, ovulation induction with gonadotrophins is associatedwith higher success rates than clomiphene citrate in IUI cycles.However, the drawbacks to the use of gonadotrophin stimulationbefore IUI include the risks of ovarian hyperstimulation andmultiple gestation, and the relative cost of a treatment cyclein view of the medication costs and the need for increased monitoringby hormone assays and ultrasonographic measurements. In thepresent prospective randomized trial, the efficacy and safetyof ovarian stimulation with clomiphene citrate (50 mg/day for5 days) and IUI (clomiphene/IUI group) were compared with thoseof late low-dose pure follicle stimulating hormone (FSH, 75IU/day from day cycle 7 until the leading follicle reached >17mm in diameter) and IUI (FSH/IUI group) in ovulatory women whowere infertile because of unexplained infertility (n=40)or malesubfertility (n =60). The mean length of treatment in the FSHgroup was 6.4±2.5 days. Multiple follicular developmentwas seen in 25% of clomiphene-stimulated cycles but only in8% of those treated with FSH. Pregnancy rate per cycle in clomiphene/IUIand FSH/IUI groups was 4% (4/98) and 13% (12/94) respectively(P=0.02). All pregnancies obtained were singleton. There weretwo and one clinical abortions in the clomiphene/IUI (50%) andFSH/IUI (8%) groups respectively. No patient developed ovarianhyperstimulation syndrome. Use of our therapeutic scheme, whichproved to be efficacious, safe and economic for ovarian stimulationin IUI cycles, is advocated before the institution of in-vitrofertilization (IVF) or gamete intra-Fallopian transfer (GIFT)therapy in infertile patients with patent Fallopian tubes. Thislate low-dose technique of administering pure FSH is suitablefor use in offices without immediate access to oestradiol results.     

Endocrinology: Effects of recombinant human follicle stimulating hormone on cultured human granulosa cells: comparison with urinary gonadotrophins and actions in preovulatory follicles

The effects of recombinant human follicle stimulating hormone(rFSH; Org 32489) have been examined in human granulosa cellsfrom ovaries obtained from women with spontaneous menses. Inthe first series of experiments the actions of rFSH on productionof oestradiol and progesterone were compared with those of urinary-derivedgonadotrophins. Recombinant FSH induced dose-dependent increasesin production of both oestradiol and progesterone which weresimilar to the effects of ’pure‘ FSH (Metrodin®)and the International Standard IS 71/223. In further studies,the actions of rFSH on oestradiol production by individual preovulatoryfollicles were investigated; rFSH increased oestradiol accumulationfrom cells obtained from follicles before the luteinizing hormone(LH) surge. In contrast, rFSH inhibited oestradiol productionby granulosa cells derived from a follicle after the onset ofthe LH surge, whereas the gonadotrophic action of growth hormonewas maintained. Following preliminary reports of the in-vivoeffects of rFSH in women, these findings provide further validationof the efficacy of rFSH in the human ovary. The results of studiesof the preovulatory follicle illustrate the experimental importanceof the availability of recombinant preparations of pure gonadotrophins,produced by recombinant technology, in the understanding ofhuman ovarian function.     

The significance of elevated basal follicle stimulating hormone in regularly menstruating infertile women

Elevated plasma follicle stimulating hormone (FSH) during thereproductive life is an early manifestation of ovarian ageing.The presence of elevated basal FSH in young, regularly menstruatingwomen may represent a stage of menopausal transition consequenton premature ovarian failure. A total of 48 regularly menstruating,infertile women aged <40 years, with high FSH and aged-matchedcontrols with normal FSH underwent detailed monitoring of endocrineand follicle growth during one complete menstrual cycle. Duringthe same cycle, detailed immunological screening was performedand the epidemiological features of all subjects were also reviewed.Subjects in the high FSH group had significantly higher basalFSH, luteinizing hormone (LH) and follicular phase LH concentrations.Despite their normal preovulatory oestradiol production, thehigh FSH group showed significantly slower follicular growth,smaller follicle diameter and lower luteal phase salivary progesterone.All these features have been described in older women duringtheir menopausal transition. In addition, the prevalence ofautoimmune antibodies was significantly higher in the high FSHgroup. This study suggests that infertile women with elevatedFSH are in their perimenopause despite having regular ovulatoryand apparently normal cycles. An autoimmune basis is suggestedas a factor underlying their premature ovarian failure. Furtherendocrinological and auto-immunological follow-up is recommended.     

Adjuvant L-arginine treatment for in-vitro fertilization in poor responder patients.

The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different ovarian stimulation protocols: (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). During the ovarian stimulation regimen, the patients were submitted to hormonal (oestradiol and growth hormone), ultrasonographic (follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluations. Furthermore, the plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate.     

Case Report: First established pregnancy and birth after ovarian stimulation with recombinant human follicle stimulating hormone (Org 32489)

This case report describes the first established pregnancy andbirth after ovarian stimulation with Org 32489, pure recombinanthuman follicle stimulating hormone (recFSH, Organon International).A patient with tubal infertility participated in an open efficacystudy of recFSH evaluating the efficacy of combined gonadotrophin-releasinghormone (GnRH)agonist/recFSH treatment in women undergoing in-vitrofertilization (IVF) and embryo transfer. Ovarian stimulationwas induced by recFSH in association with buserelin (Suprecur^®,4 x 150 µg/day) using a short protocol. After 9 days ofrecFSH treatment (75 IU/day), six pre-ovulatory follicles (15mm) were observed and 10 000 IU human chorionic gonadotrophinwere administered. Nine mature oocytes were retrieved by oocytepuncture and after IVF, three embryos were replaced in the uterus.A viable singleton intra-uterine pregnancy was revealed at agestational age of 7 weeks. The pregnancy progressed normallyand ended with a vaginal delivery at a gestational age of 39.5weeks. A healthy girl was born and paediatric examination didnot demonstrate any abnormality.     

Accuracy of ovarian reserve tests.

Several tests predict ovarian reserve in women undergoing assisted reproductive technologies. However, the accuracy of these tests in assessing the number of the remaining follicles within the ovary (ovarian reserve) has not been previously validated. The aim of this study was to assess the accuracy of ovarian reserve tests, namely basal and clomiphene-stimulated follicle stimulating hormone (FSH) concentrations and gonadotrophin-releasing hormone (GnRH) agonist stimulation test in predicting the number of the follicles within the ovaries. The ovaries of 22 parous women over 35 years of age who underwent oophorectomy were examined histologically for follicle number. Early follicular phase serum FSH, clomiphene citrate challenge tests (CCCT) and GnRH agonist stimulation test (GAST) were performed in the menstrual cycle prior to the surgery. The predictive value of these tests was then assessed. A positive correlation was detected between basal serum oestradiol concentrations and follicles per unit tissue but no significant correlation was detected between basal and clomiphene-stimulated FSH and follicles per unit tissue. The receiver operator characteristic curves indicated that the clomiphene citrate challenge test was the most accurate of the three tests assessed. In conclusion, none of the tests in this study accurately reflects ovarian reserve.     

Polycystic ovary syndrome: low-dose follicle stimulating hormone administration is a safe stimulation regimen even in previous hyper-responsive patients.

We studied 23 women with polycystic ovarian syndrome (PCOS), resistant to clomiphene citrate, who had a previous history of multifollicular ovarian development on gonadotrophin stimulation. Each woman had one cycle of gonadotrophin-stimulating hormone agonist/human menopausal gonadotrophin (GnRHa/HMG) stimulation and then one cycle of low-dose follicle stimulating hormone (FSH) stimulation. All GnRHa/HMG cycles were multifollicular. On the low-dose FSH protocol, 10 cycles were unifollicular, while two to three follicles were observed in nine cycles, and four cycles were multifollicular. The ovarian hyperstimulation syndrome ensued in one of the FSH cycles versus 13 of the GnRHa/HMG cycles. Despite decreasing luteinizing hormone (LH) levels and increasing FSH levels, androgen levels increased during stimulation on both protocols. There was one pregnancy in the GnRHa/HMG cycles versus six pregnancies following the FSH cycles. In conclusion, low-dose FSH administration seems a safe stimulation regimen with a satisfactory conception rate even in PCOS women with a previous record of multifollicular ovarian development.     

Smoking, alcohol and caffeine in relation to ovarian age during the reproductive years

BACKGROUND: We sought to determine whether smoking, alcohol and caffeine are related to four indicators of ovarian age: antral follicle count (AFC), follicle stimulating hormone (FSH), inhibin B and estradiol. METHODS: Analyses drew on ultrasound scans and sera from 188 women, aged 22-49. We used least squares regression to estimate differences in AFC and hormone levels for women who smoke cigarettes or who drink alcohol or caffeine. RESULTS: Current smoking is related to elevated FSH (beta for ln(FSH) = 0.21, 95% CI 0.04, 0.39), but not to AFC, inhibin B or estradiol. Neither alcohol nor caffeine is related to any ovarian age indicator. Exploratory analyses suggest that the association of current smoking with FSH varies with age: comparing current with never smokers, at ages 30, 35, 40 and 45, estimated differences in mean FSH are 0.3, 1.3, 3.2 and 6.9 mIU/ml. CONCLUSIONS: The association of current smoking with FSH may reflect accelerated oocyte atresia, impaired follicle quality or dysregulation of the hypothalamic-pituitary-ovarian axis. Identification of the causal mechanism has implications for prevention or treatment of conception delay, infertility and morbidity associated with early menopause.     

Ovarian response to repeated controlled stimulation in in-vitro fertilization cycles in patients with ovarian endometriosis

In-vitro fertilization (IVF) is an effective infertility treatment for women with endometriosis, but most women need to undergo several cycles of treatment to become pregnant. This case-control study was designed to assess how consistently women with ovarian endometriosis respond to ovarian stimulation in consecutive treatment cycles compared to women with tubal infertility. We compared outcome measures in 40 women with a history of surgically confirmed ovarian endometriosis and 80 women with tubal infertility, all of whom had at least three IVF treatment cycles. The groups were matched for age and early follicular follicle stimulating hormone (FSH) concentration at their first IVF cycle. Outcome measures included number of follicles, number of oocytes, peak oestradiol concentration and number of FSH ampoules required per follicle. Cumulative pregnancy and live birth rates were calculated in both groups. The ovarian endometriosis group had a significantly poorer ovarian response and required significantly more ampoules of FSH per cycle, a difference that became greater with each subsequent cycle. However, cumulative pregnancy (63.3 versus 62.6% by fifth cycle) and live birth (46.8 versus 50.9% by fifth cycle) rates were similar in both groups. In conclusion, despite decreased ovarian response to FSH, ovarian endometriosis does not decrease the chances of successful IVF treatment.     

Simultaneous induction of multiple follicular development with gonadotrophins and steroid replacement for in-vitro fertilization.

Simultaneous administration of follicle stimulating hormone, oestradiol valerate and progesterone was employed in a patient with a possible enzymatic deficiency involving low production of oestradiol. The patient became pregnant after in-vitro fertilization. This case demonstrates that this treatment is useful in women with low oestradiol production and subsequent inadequate endometrial development; it also illustrates the role of oestradiol in follicular development and questions the importance of serum oestradiol measurements in the monitoring of ovulation induction.     

case report: Ovarian stimulation in an infertile patient with growth hormone-deficient Oliver-Mcfarlane syndrome

Several authors have suggested that growth hormone may augmentovarian responses to follicle stimulating hormone in women (Homburget al., Clin. Endocrinol., 29, 1988; Ibrahim et al., Fertil.Steril., 55, 1991), and that this effect may be mediated byinsulin-like growth factor I (IGF-I) (Davoren and Hsueh, Endocrinology,118, 1986). Menashe et al. (Hum. Reprod., 6, 1991) reportedspontaneous pregnancies in women with a deficiency in growthhormone receptors and, consequently, low serum concentrationsof IGF-I. In this report, we present the case of a patient witha rare syndrome first described by Oliver and Mcfarlane (Arch.Ophthalmol., 74, 1965). The patient was shown to be growth hormonedeficient, with hypopituitarism as part of the syndrome. Adjuvantgrowth hormone did not influence her ovarian responses to exogenousgonadotrophins during assisted conception treatment, as reflectedby the required total number of ampoules of human menopausalgonadotrophin, the number of developing follicles, the rateof follicular growth and the serum oestradiol concentrations.     

Comparison of the effects of HMG or pure FSH stimulation during suppression with an LHRH agonist analogue.

Infertile patients who responded poorly in an in-vitro fertilization programme were treated with human menopausal gonadotrophin (HMG) or with pure follicle stimulating hormone (FSH) during continuous administration of a luteinizing hormone-releasing hormone (LHRH) agonist, to determine whether a low level of LH is required for follicle maturation. No statistically significant differences were detected in the dose of gonadotrophins, duration of treatment, oestradiol and LH levels, numbers of recovered oocytes, transferred embryos or fertilization rates. It is concluded that an absence of low levels of LH does not disturb follicular development in the follicular phase. Based on the low fertilization rates in the present study (0.32 with HMG versus 0.45 with FSH) the authors suggest that, as well as hormonal deficiency, other factors may also influence follicular and early embryonic development.     

Sertoli-Leydig cell tumour in an infertile patient after stimulated ovulation

A 36 year-old infertile female developed a stage IV (FIGO) ovarian carcinoma consisting of a poorly differentiated Sertoli-Leydig cell tumour after receiving one course of ovulation induction with follicle stimulating hormone (FSH), human menopausal gonadotrophin (HMG) and human chorionic gonadotrophin (HCG) followed by gonadotrophin-releasing hormone analogue (GnRHa). The patient died of liver metastasis and hepatic failure 4 1/2 months after first diagnosis, despite aggressive treatment consisting of debulking surgery and aggressive adjuvant chemotherapy.      

Effects of short-term GnRH agonist--human menopausal gonadotrophin stimulation in patients pre-treated with progestogen.

The recent use of gonadotrophin-releasing hormone agonist in a short-term regimen has allowed the effectiveness of human menopausal gonadotrophin (HMG) stimulation to be markedly improved. It seems to be related to the flare-up effect of the agonist in the early follicular phase of the cycle. However, individual hormonal responses to the agonist are quite variable and four patterns of oestradiol secretion have been described. The present study indicates that in women pre-treated with progestogen, only two patterns of serum oestradiol are observed in the flare-up period, with a significant increase in 57% of patients. Significant correlations are observed between oestradiol values and the endogenous gonadotrophin surge (positively with luteinizing hormone, r = 0.38; P less than 0.05 and negatively with follicle stimulating hormone, r = 0.48; P less than 0.005). Furthermore, there was a significant relationship between the hormonal flare-up and the ovarian parameters following HMG stimulation. In conclusion, in progestogen-pre-treated women, the serum oestradiol level during the flare-up period is a reliable index to predict subsequent effectiveness of ovarian stimulation with HMG.     

HMG is as good as recombinant human FSH in terms of oocyte and embryo quality: a prospective randomized trial

Previous studies have demonstrated that the use of recombinant human follicle stimulating hormone (rhFSH) for ovarian stimulation may be associated with a better outcome than human menopausal gonadotrophin (HMG), probably due to the absence of LH, higher FSH bioactivity and better quality of oocytes and embryos when rhFSH is used. Very few studies have examined the effects of different gonadotrophins on oocyte and embryo quality. In this prospective study, 40 women undergoing ovarian stimulation for intracytoplasmic sperm injection were randomized to receive a standard protocol of either HMG or rhFSH in down-regulated cycles. Prior to microinjection, each denuded oocyte was videotaped to assess nuclear maturity, morphology of zona pellucida, oocyte and polar body and the zona thickness, and diameters of oocyte and ooplasma. Fertilization and subsequent embryo development of each oocyte were followed. The embryologists were blind to the type of gonadotrophin each patient had received for stimulation. No significant differences were found between the two groups with regard to the demographic data, the ovarian responses and pregnancy/implantation rates. The percentage of metaphase II oocytes in the HMG and rhFSH groups were similar (86.9 versus 87.4% respectively). All other parameters assessing oocyte and embryo quality were also comparable between the two groups.     

Does growth hormone-releasing factor assist follicular development in poor responder patients undergoing ovarian stimulation for in-vitro fertilization?

Treatment with growth hormone-releasing factor (GRF) has been reported to improve the ovarian response to gonadotrophins in women who respond poorly to ovarian stimulation during in-vitro fertilization (IVF). The efficacy and tolerability of GRF were studied in a randomized, double-blind, placebo-controlled trial involving 196 patients. Following down-regulation with a gonadotrophin-releasing hormone agonist (GnRHa), patients were randomized to receive GRF (500 microg twice daily; n = 96) or placebo (n = 100) in addition to follicle stimulating hormone (FSH); treatment was continued until human chorionic gonadotrophin was given, or for a maximum of 14 days. GRF had no significant effect on the mean number of follicles with a diameter of >/=16 mm (GRF: 3.26 +/- 2.29; placebo: 3.27 +/- 2.30; P = 0.95), the number of FSH ampoules required to achieve ovarian stimulation (GRF: 55.2 +/- 16. 4; placebo: 54.9 +/- 17.2; P = 0.50), or on secondary measures of ovarian response and treatment outcome. There were, however, significant increases in circulating growth hormone (GH) and insulin-like growth factor (IGF)-1 concentrations. GRF was well tolerated. It is concluded that, despite producing significant increases in GH and IGF-1, concomitant treatment with GRF does not improve the ovarian response to FSH in poorly responsive women undergoing IVF.