Spontaneous luteinizing hormone surges can be reliably prevented by the timely administration of a gonadotrophin releasing hormone antagonist (Nal-Glu) during the late follicular phase.

A new gonadotrophin releasing hormone antagonist (Nal-Glu) was used during the late follicular phase of the natural cycle in order to prevent spontaneous surges of luteinizing hormone (LH). Eight regularly ovulating women (group 1) received two injections of Nal-Glu (5 mg) administered 48 h apart when plasma oestradiol levels exceeded 125 pg/ml. Human menopausal gonadotrophin (HMG, 225 IU) was administered simultaneously with Nal-Glu and repeated every 12 h thereafter until either a spontaneous LH surge occurred or human chorionic gonadotrophin (HCG, 5000 IU) was administered. HCG was arbitrarily administered 48 h after the second Nal-Glu injection. Six other women (group 2) receiving only HMG served as controls. In seven of the eight women in group 1, LH and progesterone remained low for 96 h following Nal-Glu, i.e. until HCG administration. In the remaining woman in this group, LH started to rise 12 h before HCG injection. In this group, Nal-Glu did not interfere with follicular development or the plasma profile of oestradiol. All women developed one single dominant follicle with the exception of one subject who had already spontaneously developed two dominant follicles prior to administration of Nal-Glu and HMG. In group 2, LH rose spontaneously in all women before the planned HCG injection. The luteal phase was apparently not altered by Nal-Glu. These results suggest that Nal-Glu administration during the late follicular phase of natural cycles supported by HMG, can prevent the spontaneous LH surge while not interfering with follicular growth.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series

In patients with poor response to ovarian stimulation with gonadotrophins, growth hormone (GH) is sometimes used to increase paracrine insulin-like growth factor-1 (IGF-1) effect. We postulated that dehydroepiandrosterone (DHEA) administration to poor responders would augment gonado-trophin effect via a similar mechanism. Baseline ovarian stimulation response to a cycle with DHEA in five healthy non-smoking women <41 years old was compared with day 3 FSH <20 mIU/ml. All had documented poor response to vigorous gonadotrophin administration. After day 2 ultrasounds, DHEA-sulphate (DHEA-S), FSH, human chorionic gonadotrophin (HCG), and testosterone were measured, and the women were given 80 mg/day of oral micronized DHEA for 2 months. While still on DHEA, they underwent ovarian stimulation with FSH given i.m. twice a day, and HCG (10 000 IU) at follicular maturity, followed by intrauterine insemination. Cycle parameters assessed were peak oestradiol, and peak oestradiol/ampoule. The DHEA/ovarian stimulation cycles occurred between 4 and 24 months after the control cycles. After 2 months DHEA treatment, DHEA-S increased to 544 +/- 55 microg/dl, and testosterone increased to 67.3 +/- 6.1 ng/dl. All five subjects (six cycles; one subject had two DHEA cycles) had increased responsiveness; peak oestradiol concentrations increased from 266.3 +/- 69.4 pg/ml to 939.8 +/- 418.9 pg/ml. The oestradiol/ampoule ratio increased in all six cycles, by a mean of 2.94 +/- 0.50 fold (P = 0.012). One of the cycles resulted in a delivered twin pregnancy. In this small series, DHEA improved response to ovarian stimulation even after controlling for gonadotrophin dose. Supplemental DHEA treatment during ovarian stimulation may represent a novel way to maximize ovarian response.     

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.     

Induction of follicular growth and production of a normal hormonal milieu in spite of using a constant low dose of luteinizing hormone in women with hypogonadotrophic hypogonadism

This study was designed to examine ovarian performance, i.e.follicular growth, normal steroidogenesis and luteal phase function,following the administration of multiple increasing doses ofhuman follicle stimulating hormone (FSH) with a constant lowdose of luteinizing hormone (LH) in women with isolated hypogonadotrophichypogonadism. Human meno–pausal gonadotrophin (HMG) wasused in the first treatment cycle, starting with 150 IU of LHand 150 IU of FSH per day, for 7 days. The dose was increaseddaily with 75 IU of LH and 75 IU of FSH for another 7 days ifno response was detected by serial ultrasound measurements andserumoestradiol determinations. In the second treatment cycle,a constant dose of 75 IU of LH (using HMG) was administeredper day and up to 150 IU of FSH (using urofollitrophin) wassupplemented. If no response was detected after 7 days of treatment,the dose of FSH was increased. For the final stage of ovulationinduction, human chorionic gonadotrophin (HCG) was administeredin the presence of at least one follicle >17 mm in diameterbut with no more than three follicles >16mm in diameter.To verify the adequacy of the luteal phase, a pharmacokinetic/pharmacodynamicstudy of -HCG, oestradiol and progesterone was performed followingthe second treatment cycle only. Ovarian stimulation using aconstant dose of 75 IU of LH and increasing doses of FSH upto 225 IU, resulted in normal follicular growth and hormonalmilieu. Both women showed normal luteal phase oestradiol andprogesterone production and both women conceived following thesecond treatment cycle     

A double-blind cross-over controlled study to evaluate the effect of human biosynthetic growth hormone on ovarian stimulation in previous poor responders to in-vitro fertilization

The effect of exogenous human biosynthetic growth hormone (HGH;12 IU/day; Norditropin, Novo-Nordisk) on the response to ovarianstimulation using a buserelin/human menopausal gonadotrophin(HMG) regimen was assessed in women who had previously showna ‘poor response’ in spite of increasing doses ofHMG. Forty patients were recruited into a prospective double-blindplacebo-controlled study. The serum follicle stimulating hormone(FSH) on day 2–5 of a menstrual cycle (< 10 IU/I) wasused to exclude any peri-menopausal candidates. The urinary24 h GH secretion was normal in all patients. Thirty-three patientscompleted the study with 21 patients having human chorionicgonadotrophin (HCG) in both arms, thus providing a completeset of placebo control data. Of these 21 patients, the administrationof HGH compared to the placebo cycle resulted in increased serumconcentrations of fasting insulin on the 8th (median 3.9 versus5.8 mU/I; P < 0.0005) and13th (median 4.4 versus 5.8 mU/I;P < 0.05) day of HMG in those cycles receiving HGH. After8 days of co-treatment with HGH the number of cohort follicles(14–16.9 mm) was significantly increased, but this changewas not sustained on the day of HCG administration. No statisticaldifference in the serum oestradiol on the 8th day of HMG orday of HCG, length of the follicular phase, total dose of HMGused, or the number of oocytes collected was seen between theplacebo or HGH cycles. This study demonstrates that HGH doesnot improve the ovarian response to ovulation induction in previouspoor responders.     

The effects of the somatostatin analogue octreotide on ovulatory performance in women with polycystic ovaries

The elevated luteinizing hormone (LH) and androgen concentrationscharacteristic of women with polycystic ovaries (PCO) are consideredcrucial factors in their infertility. The somatostatin analogueoctreotide lowers LH and androgen concentrations in women withPCO. The effects of octreotide given concurrently with humanmenopausal gonadotrophin (HMG) were therefore compared withthat of HMG alone in 28 infertile women with PCO resistant toclomiphene. In 56 cycles of combined HMG and octreotide therapythere was more orderly follicular growth compared with the multiplefollicular development observed in 29 cycles in which HMG wasgiven alone (mean number of follicles > 15 mm diameter onthe day of human chorionic gonadotrophin (HCG) administration:2.5 ± 0.2 and 3.6 ± 0.4 respectively; P = 0.026).There was a significantly reduced number of cycles abandoned(>4 follicles > 15 mm diameter on day of HCG) in patientstreated with octreotide + HMG, so that HCG had to be withheldin only 5.4% of cycles compared to 24.1% with HMG alone (P <0.05). The incidence of hyperstimulation was also lower on combinedtreatment. Octreotide therapy resulted in a more ‘appropriate’hormonal milieu at the time of HCG injection, with lower LH,oestradiol, androstenedione and insulin concentrations. Althoughgrowth hormone concentration was similar on both regimens, significantlyhigher insulin growth factor-I concentrations were observedon the day of HCG in women on combined therapy than on HMG alone.     

Non-response to ovarian stimulation in normogonadotrophic, normogonadal women: a clinical sign of impending onset of ovarian failure pre- empting the rise in basal follicle stimulating hormone levels

The most important aspect of diminished ovarian reserve is the associated decline in reproductive potential. Assessment of ovarian reserve is mainly based on measurement of early follicular phase follicle stimulating hormone (FSH) concentration. The objective of this study was to report the identification of a group of 12 infertile women initially diagnosed as having unexplained or anovulatory infertility, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins. All developed ovarian failure within a relatively short time span. Non-response to ovarian stimulation was defined by failure to achieve development of follicles >12 mm and failure to raise oestradiol concentration >350 pmol/l in two successive cycles of human menopausal gonadotrophin (HMG) doses of up to five ampoules per day for 5-8 days. Within a mean of 9 months following the failed attempts of ovarian stimulation the mean day 3 FSH concentrations rose from 5.4 +/- 2.7 IU/l to 53.5 +/- 19.7 IU/l. In these patients, day 3 FSH concentration failed to indicate the low ovarian reserve manifested only by lack of clinical response to treatment with gonadotrophins which was the first sign of impending ovarian failure. We conclude that women with normal early follicular phase serum FSH concentrations who do not respond to ovarian stimulation by HMG are at risk of developing ovarian failure within several months.      

Is continuation of a gonadotrophin-releasing hormone agonist (GnRHa) necessary for women at risk of developing the ovarian hyperstimulation syndrome?

A total of 28 women scheduled for in-vitro fertilization used buserelin and human menopausal gonadotrophin (HMG) for ovarian stimulation. One group (I) of 17 women was given human chorionic gonadotrophin (HCG 10,000 IU) to trigger ovulation, but the resulting embryos were electively cryopreserved because of the risk (serum oestradiol greater than or equal to 3500 pg/ml) of developing the ovarian hyperstimulation syndrome (OHSS). Six women continued the buserelin therapy in the luteal phase and eleven did not. In group II (n = 11), the HMG injections were discontinued because of an exaggerated ovarian response and the HCG was omitted. Six of these women continued the buserelin injections until the onset of menses and five did not. In both groups, the ovarian response to induction of ovulation (serum oestradiol concentrations and number of follicles) was similar for those who did or did not continue buserelin therapy. There was no difference in the rate of ovarian quiescence (weekly fall in serum oestradiol concentration following the stimulation) between those women who did or did not continue the buserelin therapy in either group. The serum luteinizing hormone concentrations remained low in all women in both groups. We conclude that the omission of buserelin therapy after discontinuing the HMG in women at risk of developing OHSS does not affect subsequent ovarian quiescence.     

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.     

Follicle-stimulating hormone as a prognostic indicator in clomiphene citrate/human menopausal gonadotrophin-stimulated cycles for in-vitro fertilization

Follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and prolactin levels were studied in a sequential clomiphene citrate/human menopausal gonadotrophin (CC/HMG) regimen for in-vitro fertilization. At completion of CC administration, the median FSH level in 44 cancelled cycles was elevated compared to a control group of 65 completed cycles, 29 IU/l versus 15 IU/l, P less than 0.01. Also the median FSH/LH ratio was higher in the cancelled cycles than in the control group, 1.08 versus 0.71, P less than 0.05. Conversely, the median oestradiol level was lower in the cancelled cycles than in the completed cycles, 0.27 nmol/l versus 0.59 nmol/l, P less than 0.01. No difference was seen in the median LH and prolactin levels. An FSH value above the 95% confidence limit was found in 24 of the cancelled cycles, but in only two of the completed cycles. Based on this study, an elevated FSH value following CC administration predicts a poor response to further stimulation with an accuracy of 92.3% and should result in cancellation of the cycle.     

Hormonal and histological evaluation of the luteal phase after combined GnRH-agonist/gonadotrophin treatment for superovulation and luteal phase support in in-vitro fertilization.

A hormonal and histological study of the luteal phase was performed in 21 stimulated in-vitro fertilization (IVF) patients not undergoing embryo transfer. Ovarian stimulation was carried out with gonadotrophins [follicle stimulating hormone (FSH) + human menopausal gonadotrophin (HMG)] under pituitary suppression with buserelin. Ovulation was induced with 5000 IU human chorionic gonadotrophin (HCG) and additional doses of 5000, 2500 and 2500 IU were given on the day of follicular aspiration, and 2 and 5 days later respectively, to support the luteal phase. Supraphysiological levels of oestradiol (E2) and progesterone in plasma were found in the midluteal phase of all women, while prolactin was in the normal range. An endometrial biopsy taken in the late luteal phase was normal in 90.5% (19/21) of patients, most of them (15/19, 79%) having E2 greater than 1500 pg/ml on the day of HCG. Conversely, both patients with defective endometrial biopsies had E2 levels less than 1500 pg/ml.     

Excessive follicular response to controlled ovarian stimulation in a woman with menopausal FSH levels: case report

A suspected poor responder to controlled ovarian stimulation (COS), with menopausal levels of follicular phase serum FSH, required coasting due to an excessive ovarian response. A 27 year old woman was referred to our Fertility Centre for ovum donation following repeated elevated, early follicular phase FSH levels (34.3, 27.1, 20.3 IU/l). Further investigations revealed the presence of antiovarian antibodies and a trial of COS, with the additional use of prednisolone, was proposed in view of her regular 28 day cycle. As 23 follicles were noted and an oestradiol level of 10,461 pmol/l following 7 days of stimulation with 450 IU of recombinant FSH per day, gonadotrophins were withheld for 9 days. Ten oocytes were retrieved and two grade I embryos were transferred. Pregnancy did not occur and she developed mild ovarian hyperstimulation syndrome. During a second cycle, multiple follicular development was again observed with an oestradiol level >13,200 pmol/l, despite a lower dose of gonadotrophin, and coasting was required for 4 days. Nineteen oocytes were collected, of which nine fertilized and cleaved. Two grade I embryos were replaced, leading to a singleton pregnancy. This patient subsequently had a vaginal delivery of a normal male baby at term. Young women with regular menstrual cycles and grossly elevated FSH levels may benefit from further investigation of autoantibodies and their ovarian response to exogenous gonadotrophins.     

The effect of gonadotrophins with differing LH/FSH ratios on the secretion of the various species of inhibin in women receiving IVF

We have measured secretory patterns of inhibin A, B, total alpha inhibin, pro-alphaC inhibin and oestradiol in women following pituitary suppression who were randomised into two groups to receive either urinary gonadotrophin (25:75 IU/ampoule of luteinizing hormone (LH) and follicle stimulating hormone (FSH; Normegon; n = 11) or recombinant (r)FSH (75 IU/ampoule of FSH alone, n = 16). The women were of similar age (approximately 33 years) and length of infertility (approximately 4 years) and had a normal endocrine evaluation. Plasma FSH, LH, oestradiol, inhibin A, B, pro-alphaC and total alpha inhibin were measured by immunoassay prior to and following gonadotrophin stimulation. Immunoactive FSH, LH and oestradiol blood concentrations following pituitary down regulation were similar in the two groups being <2.0, <3.6 IU/l and <82 pmol/l respectively. The units of FSH given (2230 versus 2764 IU; Normegon versus rFSH), duration of treatment (9.1 versus 9.4 days) and number of follicles of > or =14mm on the day of human chorionic gonadotrophin (HCG) administration (17 versus 14) were also similar. Inhibin A or B concentrations rose similarly during Normegon or rFSH administration, peaking at days 9-11. Total alpha and pro-alphaC inhibin concentrations were lower (P < 0.05) in the rFSH group during days 10 and 11 of treatment being 18.9 +/- 15.9 ng/ml (Normegon) and 4.6 +/- 2.8 ng/ml (rFSH) for total alpha inhibin and 8.5 +/- 6.8 ng/ml (Normegon) and 2.8 +/- 1.6 ng/ml (rFSH) for pro-alphaC inhibin on day 10. Overall, higher total alpha inhibin concentrations were associated with more mature follicles and oocytes, greater fertilization rates and better quality embryos. We conclude that inhibin A and B secretion was similar in both groups and is primarily controlled by FSH, whereas total alpha inhibin and pro-alphaC increased preferentially in the Normegon group over the rFSH group, indicating that they are, in part, stimulated by LH.     

Outcome from consecutive in-vitro fertilization/intracytoplasmic sperm injection attempts in the final group treated with urinary gonadotrophins and the first group treated with recombinant follicle stimulating hormone

In the absence of specific dose equivalency data, the aim of this study was to compare the clinical results during the cross-over from menopausal urinary products (human menopausal gonadotrophin; HMG) to recombinant follicle stimulating hormone (FSH) follitrophin beta (FSHr) in order to determine whether the manufacturer's recommendation for equivalence of ampoule to ampoule (50 IU FSHr:75 IU HMG) would prove clinically correct. A total of 353 consecutive in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment cycles was studied between 1st September 1996 and mid-February 1997. This included cycles in the last 191 women receiving HMG and the first 162 taking FSHr. All were down-regulated using a gonadotrophin releasing hormone (GnRH) agonist long protocol method from day 1 of the cycle. Greater efficacy was seen in the HMG group in terms of days of stimulation required, need to increase dosage, cycle discontinuation, number of follicles punctured, the numbers of oocytes retrieved and their quality. The hormonal response to stimulation assessed by oestradiol concentrations on days 5, 8 and day of human chorionic gonadotrophin (HCG) was significantly lower in the FSHr group. The ratio of oestradiol per follicle and per oocyte was significantly lower in the FSHr group. There was a highly significant increase in cost with FSHr therapy. Clinical pregnancy rates were 14% per cycle with FSHr and 20% per cycle with HMG.      

Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation

Natural cycles were abandoned in in-vitro fertilization (IVF) embryo transfer, due to premature luteinizing hormone (LH) surges--and subsequent high cancellation rates. In this study, we investigated the administration of a new gonadotrophin-releasing hormone antagonist (Cetrorelix) in the late follicular phase of natural cycles in patients undergoing IVF and intracytoplasmic sperm injection (ICSI). A total of 44 cycles from 33 healthy women [mean age 34.1 +/- 1.4 (range 26-36) years] were monitored, starting on day 8 by daily ultrasound and measurement of serum concentrations of oestradiol, LH, follicle stimulating hormone (FSH) and progesterone. When plasma oestradiol concentrations reached 100-150 pg/ml, with a lead follicle between 12-14 mm diameter, a single injection (s.c.) of 0.5 mg (19 cycles) or 1 mg (25 cycles) Cetrorelix was administered. Human menopausal gonadotrophin (HMG; 150 IU) was administered daily at the time of the first injection of Cetrorelix, and repeated thereafter until human chorionic gonadotrophin (HCG) administration. Four out of 44 cycles were cancelled (9.0%). No decline in follicular growth or oestradiol secretion was observed after Cetrorelix administration. A total of 40 oocyte retrievals leading to 22 transfers (55%) was performed. In 10 cycles (25%), no oocyte was obtained. Fertilization failure despite ICSI occurred in six cycles (15%). In two patients the embryo was arrested at the 2 pronuclear (PN) stage. The stimulation was minimal (4.7 +/- 1.4 HMG ampoules). A total of seven clinical pregnancies was obtained (32.0% per transfer, 17.5% per retrieval), of which five are ongoing. Thus, a spontaneous cycle and the GnRH antagonist Cetrorelix in single dose administration could represent a first-choice IVF treatment with none of the complications and risks of current controlled ovarian hyperstimulation protocols, and an acceptable success rate.     

Synchronization of endogenous and exogenous FSH stimuli in controlled ovarian hyperstimulation (COH)

We have previously observed that exogenous oestradiol can delay the intercycle increase in plasma follicle stimulating hormone (FSH). The increase in plasma FSH that follows discontinuation of exogenous oestradiol peaks after 3 days. We have now studied the possibility of using exogenous oestradiol to synchronize the increase in endogenous FSH with the onset of human menopausal gonadotrophin (HMG) treatment in controlled ovarian hyperstimulation (COH). A total of 30 women aged 35.1+/-6.3 years (mean+/-SD) undergoing ovarian stimulation received 2 mg of oestradiol valerate twice daily starting on day 25 of the previous menstrual cycle until the first Tuesday following menses. Ovarian stimulation was initiated 3 days later. On the last day of oestradiol treatment, plasma oestradiol, FSH and luteinizing hormone (LH) (mean+/-SEM) were 566+/-53 (pmol/l), 3.8+/-0.4 (IU/l) and 5.5+/- 0.8 (IU/l) respectively. After 3 days, the FSH and LH (mean+/-SEM) had increased to 6.7+/-0.7 and 6.9+/-0.7 (IU/l) respectively while oestradiol decreased to 251+/-29 (pmol/l). The mean number (+/-SEM) of HMG ampoules used was 25.1+/-2.7 and treatment lasted 11.3+/-0.9 days. Five women became pregnant for a pregnancy rate (ongoing) of 19 (15)%. If all women aged >40 years (six women who did not become pregnant) were excluded from analysis the pregnancy rate (ongoing) was 24 (19%). These results indicate that exogenous oestradiol can safely be used for the synchronization of endogenous and exogenous FSH stimuli in COH. This approach provides the practical advantage of permitting an advanced timing of the onset of COH treatments when gonadotrophin- releasing hormone (GnRH) agonists are not used, which improves treatment convenience for patients and team members alike. Further development of this model may enable control of the onset of natural cycles which may find practical applications for timing assisted reproductive techniques (intrauterine insemination or in-vitro fertilization) in the natural cycle.      

Complete and partial luteinized unruptured follicle syndrome after ovarian stimulation with clomiphene citrate/human menopausal gonadotrophin/human chorionic gonadotrophin

A total of 31 clomiphene citrate/human menopausal gonadotrophin(HMG)/human chorionic gonadotrophin (HCG)-stimulated cyclesin 28 patients were investigated to determine the fate of eachof the matured follicles. A standard stimulation regimen wasadhered to, and ultrasound as well as hormonal monitoring wasperformed. All follicles were measured by vaginal ultrasoundat –12, +35 and +45 h relative to HCG administration andat 7 days after HCG administration. Of the 220 follicles, 107(48.6%) ruptured. The number of ruptured follicles per cyclewas correlated with the mid-luteal progesterone concentration(r = 0.63, P = 0.0005). The probability of follicular rupturewas related to follicular diameter at 12 h before HCG administration;6% of follicles <12 mm in diameter ruptured compared with87% of follicles 18–19 mm. A complete luteinized unrupturedfollicle (LUF) syndrome was observed in six cycles (20%). Inthese cycles, follicular growth and oestradiol, progesterone,luteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations at 12 h before HCG administration were similarto those in cycles with follicular rupture. However, mid-lutealprogesterone concentrations were lower in complete LUF cycles(46.97 ± 8.95 nmol/1 versus 108.74 ± 12.27 nmol/1;P = 0.02). These data demonstrate that in stimulated cyclesmany follicles, usually the smaller ones, fail to rupture, evenafter HCG administration. Complete LUF syndrome, despite a strongexogenous ovulatory signal, and the absence of any differencein peri-ovulatory hormonal parameters, indicates that the defectcausing LUF resides in the follicle itself and/or hormonal changesduring the follicular phase.     

Human prolactin release induced by follicle stimulating hormone, luteinizing hormone and human chorionic gonadotrophin

Plasma prolactin levels rise in stimulated cycles. To clarifythe effects of gonadotrophin on the lactotrophs, three studieswere performed. First, plasma concentrations of prolactin duringclomiphene citrate (CC)-human menopausal gonadotrophin (HMG)-humanchononic gonadotrophin (HCG) treatment of women enrolled forin-vitro fertilization (IYF) were compared with those duringHMG-HCG administration while under pituitary suppression witha gonadotrophin releasing hormone (GnRH) analogue (buserelin).Women suppressed with buserelin had higher basal levels of PRLin plasma (14.4 ± 4.3 nglml versus 6.9 ± 1.4 ng/ml,P<0.001). Only buserelin-suppressed women showed a significantrise in plasma prolactin before HCG administration, while bothpatient groups had marked prolactin peaks after HCG injection.This peak was higher in the buserelin group (71.9 ± 50.7ng/ml versus 52.6 ± 29.7 ng/ml). The second study showedthat plasma levels of prolactin of 6 post- menopausal womenwere significantly increased 48 h after an injection of 5000IU HCG, i.m. (24.9 ± 17.4 ng/ml versus 12.4 ±6.2 ng/ml P<0.05). Third, plasma prolactin was studied in5 women over 30 days after surgical castration. An upward trendwas observed similar to that of endogenous gonadotrophin, withthe change in prolactin values closely correlating with thechange in concentrations of follicule stimulating hormone (P<0.005).All these findings suggest that human gonadotrophins stimulatelactotrophs.     

Premature luteinization of follicles during ovarian stimulation for in-vitro fertilization

The structure and growth of developing follicles was monitored using vaginal ultrasound scanning in an outpatient programme of in-vitro fertilization (IVF) and embryo transfer (ET). Patients received either human menopausal gonadotrophin (HMG) alone or clomiphene citrate (CC) + HMG for controlled ovarian stimulation. Ultrasound data were compared with pre-ovulatory oestradiol (E2), luteinizing hormone (LH) and progesterone (P) levels. Hormonal parameters and results were classified according to the main indications of IVF-ET treatment. Twenty-one of the 271 patients in the study showed ultrasonic evidence of premature luteinization (PL) of follicles, thickening of the follicular wall and the appearance of irregular echogenic structures in the follicle. PL was preceded in eight cases by an indisputable LH surge and subsequent P elevation. In the remaining 13 cases PL occurred either due to an abortive LH surge not exceeding by 3-fold the baseline values or as a result of HMG administration. Special attention was paid to the P pattern prior to and after human chorionic gonadotrophin (HCG) administration. PL cycles demonstrated significantly (P less than 0.05) higher P levels before HCG administration and at the time of oocyte retrieval as well. Because implantation was not achieved in these cases, the cancellation of PL cycles is recommended. Vaginal ultrasound scanning seems to be helpful in the evaluation of minor changes in the follicular structure, correlating frequently with hormonal findings.     

Endocrinology: The effect of growth hormone on granulosa cell function during in-vitro fertilization

The effect of growth hormone addition to human menopausal gonadotrophin(HMG), after pituitary down-regulation, on granulosa cell function,in in-vitro fertilization (IVF) was evaluated. Growth hormoneor placebo were added in a prospective, randomized and double-blindmanner to an existing IVF stimulation protocol. Forty-two normalovulatory women (38 years old) with mechanical factor infertilityand normal male factor were included in the study. Gonadotrophin-releasinghormone agonist (GnRHa) was given from day 21 of the previouscycle until human chorionic gonadotrophin (HCG) administration.Follicular stimulation with HMG was started after pituitarydown-regulation. Growth hormone 12 IU/day or placebo were administeredon alternate days, beginning day 1 until day 7 of HMG treatment.Granulosa cell function was evaluated, in all patients, by follicularfluid levels of ovarian steroids and insulin-like growth factor-I(IGF-I). In 14 patients, chosen arbitrarily granulosa luteincells were cultured in the presence and absence of additionalHCG. Follicular fluid levels of oestradiol, progesterone, testosteroneand IGF-I were similar in both growth hormone and placebo groups.Basal and post-HCG levels of oestradiol and progesterone didnot differ significantly between the two groups of granulosalutein cell cultures. We conclude that after pituitary down-regulation,in-vivo administration of growth hormone with HMG in young ovulatorywomen does not seem to affect granulosa cell function when comparedto the administration of HMG alone.