Antenatal Diagnosis of Dizygotic, Monochorionic Twins Following IVF/ICSI.

Monochorionic twins are usually monozygotic and thus usually have the same sex. A case of monochorionic diamniotic twins following IVF/ICSI and laser treatment of the zona pellucida ("assisted hatching") is presented in which partial embryo amalgamation appears to have occurred. Discordant sex between the twins was suspected on detailed antenatal ultrasound at 13 + 3 weeks gestation and was confirmed on subsequent examinations. The sexual phenotype at birth was female for one twin and male for the other. Placental histology confirmed the monochorionic, diamniotic situation. Cytogenetic analysis of both twins was carried out postpartum on various tissues. On karyotyping of blood lymphocytes the male and female twins each had one mosaic of male and female cells. Oral mucosal cells showed normal male and female karyotypes respectively. Analysis of urothelium showed a normal result for the male infant, and a weak gonosomal mosaic with an XX and XY constellation for the female infant. At least for blood lymphocytes, a diagnosis of chimerism was proven.

Early onset and high prevalence of gestational diabetes in PCOS and insulin resistant women before and after assisted reproduction.

OBJECTIVES: Polycystic ovary syndrome (PCOS) and/or insulin resistance (IR) are frequent conditions in women choosing assisted reproduction techniques (ART). However, infertility work-up has to include testing of insulin sensitivity to diagnose IR. It was the aim of the study to analyze the frequency of impaired glucose tolerance (IGT) or gestational diabetes (GD) in the first weeks of gestation after ART in women receiving metformin. DESIGN AND METHODS: This study included 107 women who were seeking ART under the pretreatment of metformin for PCOS, confirmed IR, recurrent spontaneous miscarriages (RSA) or other fertility disorders. They were examined for prepregnancy health parameters (weight, glucose tolerance). When pregnancy was confirmed a 75 g oral glucose tolerance test (OGTT) was conducted between the 5(th) and 7(th) week of gestation. RESULTS: A high rate of GD or IGT already was observed in the first weeks of pregnancy in our cohort under metformin treatment. The predominant risk factor for diagnosed early onset of IGT or GD (58 cases) was PCOS (p=0.014). The frequency of GD was the highest in the subgroup with prepregnancy confirmed IR not fulfilling the criteria of PCOS (55%); it was 40.6% in PCOS women and 26.1% in women neither exhibiting IR nor PCOS. CONCLUSIONS: Women seeking ART and being treated with metformin still show a very high rate of GD or IGT after achieving pregnancy by ART. Therefore in women undergoing ART screening for GD should be performed as soon as pregnancy is confirmed to avoid miscarriages due to overlooked uncontrolled glucose metabolism.

ApoA-I-binding protein (AI-BP) and its homologues hYjeF_N2 and hYjeF_N3 comprise the YjeF_N domain protein family in humans with a role in spermiogenesis and oogenesis.

The screening for additional human YjeF_N domain containing proteins beside the apolipoprotein A-I interacting protein (AI-BP), identified two other genes designated hYjeF_N2-15q23 (formerly human homologue of yeast edc3) and hYjeF_N3-19p13.11 comprising the human YjeF_N family. AI-BP is ubiquitously expressed, with a predominance of these tissues where the homologues were found to be restricted including brain, mammary gland, testes and ovaries. Immunohistochemistry of human testes and ovaries showed an expression of hYjeF_N3-19p13.11 only in Leydig cells and theca cells, respectively, indicating a role in steroid hormone metabolism. Interestingly, the protein was also strongly expressed in Leydig cell tumors and in thecofibromas. The identification of hYjeF_N2-15q23 in theca cells and granulosa cells in ovaries, in human spermatids of meiotic division part II and the apical membrane of Sertoli cells in testes suggest similar functions in oogenesis and sperm maturation which is strengthened by the identification of the spermatogenesis regulator HMGA1 as a conserved transcription factor. However, in contrast to AI-BP, both homologous proteins are unable to bind apoA-I. These results relate the human YjeF_N domain containing protein family to cholesterol processing and steroid hormone metabolism in spermiogenesis and oogenesis, and AI-BP may link this function to the HDL pathway.

Quality of life in elderly men with androgen deficiency.

The partial androgen deficiency in aging male (PADAM) has been of great interest to investigators and the public in the last few years. For males, androgens are said to be essential for the maintenance of quality of life (QoL) but there are no data available with respect to QoL and PADAM yet. In order to evaluate changes of individual well-being of males older than 50 years and with subnormal levels of free testosterone (FT) (<200 pmol l(-1)), these men were asked to fill in a questionnaire regarding QoL. The objective of this study was to compare age-matched males with androgen deficiency (group 1; n = 24) and normoandrogenic elderly men (group 2; n = 24) with respect to QoL and somatic indicators of the endocrine status. Participants suffered from benign prostatic hyperplasia (BPH) and were hospitalized for prostate surgery. Health-related QoL was assessed by the SF-12 Health Survey, including the physical health index and the mental health index. The SF-12 was enlarged by the scales 'vitality' and 'psychological well-being' of the SF-36. Additionally, patients were asked about social and clinical items. There were no statistically significant differences between the two groups regarding social and clinical parameters. The physical health index was reduced in group 1 (P < 0.05; effect size was medium (d = 0.57)) whereas the mental health index was similar in both groups. The correlation between the two health indices was very low and not statistically significant (r = 0.05, P = 0.72). Patients of group 1 described a lower vitality compared to group 2 (P < 0.05), but no differences could be observed regarding psychological well-being. Therefore, androgen-deficient patients seem to have the impression of a reduced physical ability. Our data emphasize that the subjective description of health-related aspects of QoL is a very sensitive methodological approach to discover psychological differences between patients. For the differentiation between androgen-deficient patients and those with normal testosterone levels the physical health index seems to be more sensitive than the mental health index. A question of interest is whether this difference remains detectable if testosterone is supplemented to androgen-deficient men. Whether testosterone supplementation is beneficial to these patients has to be carefully considered.

Rational approach to genetic testing of cystic fibrosis (CF) in infertile men.

Male infertility as a result of isolated congenital bilateral absence of the vas deferens (CBAVD) is one primary genital form of cystic fibrosis (CF) and occurs in 1-2% of infertile men. Assisted fertilization in patients with CBAVD increases the risk of transmitting mutations in the CF gene. We developed a rational approach to genetic CF testing in infertile men. A total of 282 infertile male patients were screened for the most common CF mutations (DeltaF508, R117H, IVS8-5T). Clinical data including medical history, examination, semen analysis, sweat tests, karyotypes and hormonal values were analysed. We identified 23 patients carrying mutations in the CF gene (DeltaF508: 10 patients; R117H: six patients; IVS8-5T: 11 patients). Two patients were compound heterozygote for DeltaF508/R117H, two others for DeltaF508/IVS8-5T. Correlating these molecular analyses with the clinical data pertaining to serum follicle-stimulating hormone concentration, semen pH, sperm count and total testicular volume, we were able to develop a score with a high specificity (98.4) for the presence of a cystic fibrosis transmembrane conductance regulator (CFTR) mutation, but only with a low sensitivity (positive post-test likelihood: 62.5%; negative post-test likelihood: 6.3%). With regard to the low sensitivity and the high number of CFTR mutations found in this heterogeneous group of infertile men, we still recommend genetic CF testing before assisted fertilization.

Outcome of ICSI cycles using frozen-thawed surgically obtained spermatozoa in poor responders to ovarian stimulation: cancellation or proceeding to ICSI?

OBJECTIVE: To investigate the ICSI outcome of the patients who produced four follicles or less after ovarian stimulation using frozen-thawed surgically obtained spermatozoa. STUDY DESIGN: The patient cohort of this study was composed of a carefully selected group of 20 men suffering from obstructive and non-obstructive azoospermia and in whom spermatozoa had been seen in their harvested epididymal aspirates and testicular tissues and the cryopreserved specimens had been used for subsequent ICSI cycles. This group of men represent those in whom the female partners produced only four follicles or less after ovarian stimulation. RESULTS: For the cases of obstructive azoospermia with MESA (n=6) a total of nine cycles was carried out. Four couples went through one cycle, one couple underwent two cycles, one couple accomplished three cycles. Out of the nine cycles, seven went to embryo transfer. No pregnancy occurred in the MESA-ICSI group of patients. The mean+/-S.D. number of oocytes per cycle was 2.556+/-1.236, the mean+/-S.D. number of embryos per transfer was 1.444+/-1.014. Two couples did not have an embryo replacement because of absence of fertilisation. The mean+/-S. D. number of gonadotropin ampoules was 53.88+/-37.30 and the mean+/-S.D. duration of ovarian stimulation was 13.38+/-4.534 days. For the cases of non-obstructive azoospermia with TESE (n=14) a total of 16 cycles was carried out. Thirteen couples went through one cycle, one couple accomplished three cycles. Out of the 16 cycles, 11 cycles went to embryo transfer. One pregnancy occurred in the TESE-ICSI group of patients, which produced live offspring. The mean+/-S.D. number of oocytes per cycle was 3.00+/-1.211, the mean+/-S.D. number of embryos per transfer was 1.313+/-1.195. Five couples did not have an embryo replacement, four of them because of absence of fertilisation and one because of abnormal fertilisation (3 PN). The mean+/-S.D. number of gonadotropin ampoules was 81. 77+/-53.40 and the mean+/-S.D. duration of ovarian stimulation was 16.71+/-3.667 days. CONCLUSION: In our opinion, these data show that it is possible to achieve satisfactory fertilisation rates using frozen-thawed epididymal and testicular spermatozoa obtained from men with obstructive or non-obstructive azoospermia, but the limiting factor in reaching the stage of embryo transfer is the poor ovarian response to stimulation induction. It therefore seems preferable to cancel these cycles, in the hope that a better response might be obtained in a subsequent cycle, avoiding in this way financial and emotional implications.

Comparative study of disomy and diploidy rates in spermatozoa of fertile and infertile men: a donor-adapted protocol for multi-colour fluorescence in situ hybridization (FISH).

Spermatozoa from seven healthy donors (two of whom had already fathered children) and five infertile patients taking part in the local programme of intracytoplasmic sperm-injection (ICSI) were investigated for the disomy rates of chromosomes 13/21, 18, X and Y as well as for the diploidy rates. Two- and three-colour fluorescence in situ hybridization (FISH) was applied after a donor-adapted decondensation pre-treatment: in a preliminary decondensation series the optimum fluorescence signals were individually determined by variation of the concentration of the decondensation reagents and the duration of incubation with these reagents. Strict scoring criteria were applied. The average disomy rates ranged from 0.10% (chromosomes 13/21) to 0.44% (disomy XY) in the infertile donors and from 0.07% (disomy XX) to 0.36% (disomy XY) in the controls. The average diploidy rates were 0.22% and 0.20% for the infertile donors and the controls respectively. There was no statistically significant difference between the two groups with respect to the disomy and diploidy rates. Within the two groups there were inter-individual differences which were partly statistically significant, indicating considerable inter-donor variation of the aneuploidy rates.

Significance of mutations in the androgen receptor gene in males with idiopathic infertility.

Abnormal human spermatogenesis is caused by a variety of genetic and acquired conditions. Because spermatogenesis is dependent on androgens, some males may have a minimal form of androgen insensitivity that does not inhibit virilization but impairs fertility. This has lead us to investigate the possibility of abnormalities in the androgen receptor (AR) gene in a large cohort of males suffering from infertility of unknown cause. We studied 180 males with variable impairment of spermatogenesis. In all patients, serum levels of testosterone and gonadotropins were analyzed to define an androgen sensitivity index (ASI). Single-strand conformation analysis and direct DNA sequencing of PCR-amplified blood leukocyte DNA were used to identify mutations within the whole coding region of the AR-gene. Endocrine and molecular investigations were compared with 53 normal males with proven fertility. In three infertile males, mutations in the AR were identified. Two unrelated males had the same variation within the first exon encoding for the transactivation domain of the receptor (Pro390Ser), whereas, in the third, a mutation in the hormone-binding region was characterized (Gln798Glu). All identified mutation carriers had a significantly elevated ASI. A proportion of males with idiopathic infertility carry relevant variations within the AR-gene. These males may be distinguished on the basis of hormone levels, calculating the ASI, although this index lacks specificity.

Use of frozen-thawed testicular sperm for intracytoplasmic sperm injection.

OBJECTIVE: To determine the feasibility of using frozen-thawed testicular spermatozoa for intracytoplasmic sperm injection. DESIGN: Prospective clinical study. SETTING: A university hospital. PATIENT(S): One hundred seventy-five azoospermic men participating in a routine intracytoplasmic sperm injection program. INTERVENTION(S): The men underwent testicular biopsy for cryopreservation of tissue to be used in consecutive intracytoplasmic sperm injection treatment cycles. Their female partners underwent controlled ovarian hyperstimulation for conventional IVF treatment. MAIN OUTCOME MEASURE(S): Fertilization and pregnancy rates. RESULT(S): In 77% of the patients, spermatozoa could be harvested from the testis by an open testicular biopsy technique and used for intracytoplasmic sperm injection after freezing and thawing of testicular tissue. Histopathologic evaluation revealed a Sertoli cell-only pattern in 21%, maturation arrest in 60%, and hypospermatogenesis in 19% of the patients. In 2. 9% of the patients, carcinoma in situ or a germ cell tumor was detected. In all patients, viable spermatozoa could be visualized after the tissue samples were thawed. One hundred thirty-five intracytoplasmic sperm injection treatment cycles were performed, with a fertilization rate of 45% and a clinical pregnancy rate of 30% per oocyte retrieved. CONCLUSION(S): The use of frozen-thawed testicular tissue allows ovarian stimulation of the female partner to be timed and avoids cancellation of ovum pick-up when spermatozoa cannot be retrieved.

Intracytoplasmic injection of round and elongated spermatids from azoospermic patients: results and review.

Microinjection is established as the method of choice in the treatment of severe male factor infertility as well as in azoospermic patients. Recent studies have shown that fertilization and cleavage can be achieved by injection of ejaculated as well as testicular elongated spermatids into oocytes. Here we report on the two first pregnancies worldwide resulting from elongated spermatid injection from frozen-thawed testicular tissue. Four patients with complete Sertoli cell-only syndrome (SCOS) and two with spermatogenetic maturation arrest were included in our microinjection programme. Tissues from open testicular biopsies were cryopreserved until the time of follicle puncture. A total of 67 oocytes were harvested. In the two patients with maturation arrest, cryopreserved elongated spermatids were successfully injected, while in two of the other four SCOS patients only cryopreserved round spermatids were available to be injected into the oocytes. Out of 18 injected oocytes, 10 were fertilized in the first group, while nine out of 49 injected oocytes showed fertilization and cleavage in the second group. Two clinical pregnancies were achieved with elongated spermatids from frozen-thawed testicular tissue, while no pregnancy was established in the case of round spermatids. This study confirms that fertilization, cleavage and pregnancy can be successfully achieved in cases with spermatogenetic maturation arrest by injecting cryopreserved elongated spermatids into oocytes. The literature on pregnancies following spermatid injection, as well as the problems using this technique and possible risks, are discussed.

A simple, inexpensive and effective artificial cycle with exogenous transdermal oestradiol and vaginal progesterone for the transfer of cryopreserved pronucleated human oocytes in women with normal cycles.

Supernumerary pronucleated stage oocytes (PN) are usually cryopreserved. PN are transferred in spontaneous, stimulated or artificial cycles. In this study, an artificial cycle with a transdermal therapeutic system was used for oestradiol release (Estraderm TTS 100) in combination with a targeted drug delivery system for vaginal progesterone release (Crinone 8%). Patients started transdermal 17beta-oestradiol treatment on cycle day 1. Only one clinical monitoring was necessary on day 14 for confirmation of satisfactory endometrial development and exclusion of ovulation by transvaginal ultrasound and endocrine determinations (oestradiol, progesterone and luteinizing hormone). Embryo transfer was performed on the third day of progesterone treatment (day 17). The first 25 cycles were recently completed in a prospective study; no cycles were cancelled due to ovulation or unsatisfactory endometrial development. In comparison with the previous protocol of embryo transfer in stimulated cycles in our clinic which required extensive ultrasound and endocrine monitoring, the pregnancy rate in these oestrogen- and progesterone-supplemented cycles was nearly twice as high (34.8%). Two pregnancies were even achieved with zygotes after micro-injection of frozen-thawed late spermatids extracted from testicular tissue (cryo-TESE). In these cycles, the Estraderm TTS 100/Crinone 8% protocol seems to be superior to stimulation protocols and even to other protocols reported so far for artificial cycles with exogenous oestradiol and progesterone treatment.

Pregnancies achieved after frozen-thawed pronuclear oocytes obtained by intracytoplasmic sperm injection with spermatozoa extracted from frozen-thawed testicular tissues from non-obstructive azoospermic men.

The use of frozen-thawed testicular tissue as a source of spermatozoa for intracytoplasmic sperm injection (ICSI) in non-obstructive azoospermia yields favourable fertilization and pregnancy rates while avoiding both repetitive biopsies and unexpected cycle cancellations. Spermatozoa were obtained from frozen-thawed testicular biopsy specimens from 67 non-obstructive azoospermic men. Following fertilization, supernumerary two pronuclear (2PN) oocytes were frozen. After thawing, 17 cycles of embryo transfer were carried out with a mean number of 2.7 embryos and a mean cumulative embryo score (CES) of 18.3 per transfer. The clinical pregnancy and implantation rates per transfer in these cycles (23.5 and 8.3% respectively) were comparable to those of fresh embryo transfers (35.7 and 12.7% respectively) with a mean number of 2.7 embryos and a mean CES of 28.7 per transfer. Abortion rates, although higher with cryopreserved 2PN oocytes were not significantly different. With this approach, cryopreservation of supernumerary 2PN oocytes can be used to improve the cumulative pregnancy rates in a severely defective spermatogenetic population. To our knowledge, these are the first pregnancies reported which have been obtained by the transfer of cryopreserved pronuclear oocytes obtained from ICSI using cryopreserved testicular spermatozoa.

Episodic variations of prolactin, thyroid-stimulating hormone, luteinizing hormone, melatonin and cortisol in infertile women with subclinical hypothyroidism.

Preliminary data have suggested that female infertility due to corpus luteum insufficiency may be caused by subclinical hypothyroidism [exaggerated thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) stimulation]. L-Thyroxine supplementation has been recommended to achieve pregnancies in subclinical hypothyroid women. This controlled study was carried out in order to investigate the biochemical diagnosis of subclinical hypothyroidism as a possible infertility factor. Five infertile patients (aged 25-36 years) with subclinical hypothyroidism (n = 4, stimulated TSH >20 microU/ml) or primary hypothyroidism (n = 1) and five healthy controls (aged 22-39 years) with normal thyroid function (stimulated TSH <15 microU/ml), regular cycles and no history of infertility were studied in the early follicular phase. In the pre-study evaluation, eight of 23 volunteers (34.8%) had to be excluded because of subclinical hypothyroidism with stimulated TSH values (TSHs) >15 microU/ml. Cycle function of patients and controls was compared by the method of LH pulse pattern analysis. Therefore blood samples were drawn every 10 min during a 24 h period. Sleep was recorded from midnight to 7 a.m. Repetition of the TRH tests at the end of the 24 h blood sampling period confirmed the difference in stimulated TSH values of the two study groups. Pulse analysis for luteinizing hormone (LH), TSH and prolactin showed no differences between patients and controls for pulse frequency, amplitude, height, length, area under curve (AUC) and the 24 h mean. Even the hypothyroid patient had a normal LH pulse pattern. Additional measurement of melatonin in pooled sera every 30 min gave the well-documented diurnal profiles during day and night for both groups. Patients had significantly higher melatonin values at seven time points during the night. Peaks for LH, TSH, prolactin and cortisol were correlated with the sleep stages wake, rapid eye movement, 1 + 2 and 3 + 4. We concluded that corpus luteum insufficiency in female infertility cannot be explained by subclinical hypothyroidism and thus should not be treated with L-thyroxine for fertility reasons.

Molecular cytogenetic diagnostics in sperm.

Among other factors contributing to male infertility, chromosomal anomalies are a frequent finding. Investigating 440 males with reduced sperm counts (< 20 x 10(6)/mL) we found 19 males with chromosome abnormalities (aneuploidies and translocations). This frequency of chromosomal aberrations (4.3%) is much higher than in the normal population. We were able to investigate sperm nuclei from seven out of these 19 men with molecular cytogenetic methods. There were two carriers of Robertsonian translocations, two had a constitutional reciprocal translocation and three were XYY males. In addition, one other man with a long history of infertility and a marker chromosome 15 was included. Using fluorescence in-situ hybridization, it was possible to investigate a great number of sperm nuclei in each case. Each translocation case showed a specific mode of chromosomal segregation; confirming the dependence on chromosomes involved and the individual segregation pattern in each patient. The well known elimination of the supernumerary Y-chromosome in XYY males during meiosis was confirmed in our study. Molecular cytogenetic investigations in sperm provide a more reliable risk estimate with respect to the possible injection of chromosomally unbalanced sperm during intracytoplasmatic sperm injection and can be valuable in genetic counselling.

Experience with transvaginal ultrasound-guided aspiration of supernumerary follicles for the prevention of multiple pregnancies after ovulation induction and intrauterine insemination.

OBJECTIVE: To avoid multiple pregnancies caused by ovulation induction. SETTING: Infertile couples treated in the Women's Hospital and the Institute of Reproductive Medicine of the University of Münster, Münster, Germany. DESIGN: The outcome of ovulation induction in patients in whom supernumerary ovarian follicles were aspirated transvaginally was compared with the outcome in patients in whom this intervention was not necessary. In a second randomized prospective study, the efficacy of a low dosage of gonadotropins was compared with a higher dosage. PATIENTS: Two hundred twenty-seven couples suffering from male infertility, unexplained infertility, incipient ovarian failure, and polycystic ovaries. INTERVENTIONS: Aspirations were performed if more than three follicles were sized > 14 mm. MAIN OUTCOME MEASURE: Number of (multiple) pregnancies. RESULTS: During 232 ovulation inductions, 127 aspirations of supernumerary follicles were performed (54.7%). The pregnancy rate (PR) in these cycles was similar to cycles in which aspirations were unnecessary (24.4% versus 21.9%). The efficacy of 75 units of FSH administered daily during the recruitment phase of follicular development was equivalent to 150 units of FSH (PR: 32.4% versus 31.6%), but supernumerary follicles were fewer (26.5% versus 76.3%). Six twins, two triplets (multiple PR: 10.4%), and no ovarian hyperstimulation syndrome occurred. CONCLUSIONS: Transvaginal aspiration of supernumerary follicles does not reduce the PR in ovulation induction. Supernumerary follicles can be avoided by low-dose administration of gonadotropins without compromising the PR.

Intermittent Cushing's disease in hirsute women.

Clinical symptoms of Cushing's syndrome were recognized in approximately 23 of 97 successive hirsute women attending the Endocrinological Department of the Women's Hospital. Endocrine and radiological examinations ultimately confirmed Cushing's syndrome caused by pituitary microadenomas (Cushing's disease) in only 2 women. In 17 of the remaining 21 patients suspected of having Cushing's disease hypercortisolism could not be diagnosed by classical endocrine tests. Thus further endocrinologial tests as corticotrophin releasing hormone (CRH)-tests (100 micrograms i.v.) and insulin tolerance tests were initiated including serum and stress-free salivary cortisol profiles during the day. Diurnal cortisol profiles showed higher values in the morning than during the night, but intermittent elevated cortisol concentrations could be detected. Finally, seven patients could be classified as suffering from a special form of pituitary ACTH-dependent hypercortisolism, named intermittent Cushing's disease (ICD). It is characterized by severe Cushingoid symptoms like marked central adiposity, purple striae, hirsutism and acne, intermittently increased cortisol concentrations, no cortisol response to hypoglycaemia, but preservation of some diurnal variation of serum or saliva cortisol. Three of these seven patients had diagnostic transsphenoidal neurosurgery and pituitary ACTH-producing microadenomas were removed in two women. Repeated determinations of the circadian rhythm of cortisol in saliva samples in combination with an overnight 1 mg dexamethasone suppression and an insulin stimulation test, are recommended to diagnose patients with suspicion on ICD even in an outpatient clinic.

[Restitutive effect of sleep on chronic performance stress]. / Zur restitutiven Wirkung des Schlafs bei chronischem Leistungsstress.

During a polysomnographic (2 nights) sleep registration of 5 chronically stressed compared to 5 control persons 24 h blood cortisol values and salivary cortisol at daytime were measured and compared with measured stress vulnerability. While daytime cortisol levels were reduced under stress conditions, during night sleep combined with a significant change in sleep architecture cortisol excretion raised markedly compared to controls, and the cortisol response to CRF provocation is no more blunted but activated beyond controls, demonstrating the restitutive and protective effect of sleep.

[Recombinant growth hormone for support of ovarian gonadotropin treatment in a hypophysectomized patient: a case-control study]. / Rekombinantes Wachstumshormon zur Unterstützung der ovariellen Gonadotropinbehandlung bei einer hypophysektomierten Patientin: ein Fallbeispiel mit Eigenkontrolle.

In a patient, suffering of apituitarism after the surgical removal of a cranyopharyngeoma at the age of 14, was treated with various doses of human urinary gonadotropin preparations for in vitro fertilization and embryo transfer. The first five treatments were performed without the additional administration of recombinant growth hormone, but due to the administration of increasing doses of exogenous gonadotropins a pregnancy was finally achieved leading to the birth of a healthy girl. Later, as the couple desired a second baby, the treatment was repeated using a low dose of gonadotropins in combination with recombinant growth hormone. This combined treatment was immediately successful, leading to the birth of a healthy boy. The present communication offers a complete survey of the existing literature about the use of recombinant growth hormone in support of ovarian stimulation with gonadotropins. The ongoing controversy is caused by the lack of an established methodology for the diagnosis of growth hormone deficiency. Whereas the efficacy of the additional use of recombinant growth hormone in support of ovarian stimulation with gonadotropins is established in patients without any endogenous growth hormone secretion, its use in patients with less defined hormonal disturbances remains controversial.

Pulsatile subcutaneous versus bolus intramuscular gonadotrophin administration after pituitary suppression with a long-acting gonadotrophin-releasing hormone analogue: a controlled prospective study.

The potential advantages of pulsatile s.c. administration instead of daily bolus i.m. administration of human urinary gonadotrophin preparations were tested after the administration of a long-acting gonadotrophin-releasing hormone (GnRH) analogue within a programme for in-vitro fertilization (IVF) and embryo transfer. First, the pharmacokinetic properties of human urinary gonadotrophins were analysed with immunological and biological methods, both during bolus i.m. injections and during pulsatile s.c. administration. Second, a prospective randomized controlled study was performed in 75 patients undergoing IVF/embryo transfer in whom the effects of pulsatile s.c. administration were compared with the effects of single daily bolus i.m. injections of the same gonadotrophin preparation. The results showed that neither method of gonadotrophin administration induced measurable changes in the serum concentration of luteinizing hormone (LH). Both oestradiol and androstenedione concentrations were slightly lower during pulsatile s.c. gonadotrophin administration, suggesting that this method of gonadotrophin administration results in less LH occupying the ovarian LH receptors. Pulsatile s.c. gonadotrophin administration resembles a continuous infusion of follicle-stimulating hormone (FSH). Significant fluctuations in the serum concentrations of FSH were observed during single daily bolus i.m. administration of human urinary gonadotrophins, but the pregnancy rate of IVF/embryo transfer per cycle after pulsatile s.c. administration was not significantly better than after the daily bolus i.m. injection of gonadotrophins (42.1 versus 37.2%). It is concluded that pulsatile s.c. administration of gonadotrophins instead of single daily injections does not improve the pregnancy rate in IVF/embryo transfer.

Predictive parameters for ovarian response to hyperstimulation with exogenous gonadotropins after suppression of gonadotropin secretion of the pituitary using a long-acting GnRH agonist.

Individually adapted gonadotropin dosage is more successful than standardized schemes for ovarian stimulation prior to in vitro fertilization and embryo transfer. Unfortunately, differences in ovarian response can not be predicted reliably. In order to develop predictive parameters for ovarian response the data from 99 cycles in 69 patients were analysed retrospectively. Before initiating ovarian stimulation for in vitro fertilization, an untreated menstrual cycle was examined using a commonly used endocrinological screening protocol. The ovaries were then stimulated with exogenous gonadotropins after previous suppression of endogenous gonadotropin secretion using a long-acting GnRH-analogue. The predictive value of this endocrinological screening protocol for ovarian response was evaluated. Ovarian response was defined as the logarithmically transformed ratio of the serum estradiol concentration at ovulation induction, divided by the number of ampoules of exogenous gonadotropins administered. Comparison of the various hormone characteristics with ovarian response led to identification of two distinct groups of patients showing reduced ovarian response: those with elevated serum levels of FSH on the third cycle day (> 9 units/l, P < 0.0001), and those with elevated serum levels of estradiol on the third cycle day (> 190 pmol/l, P < 0.02). Patients with high serum levels of TSH in the TRH test responded poorly to ovarian stimulation (P < 0.05), but also showed significantly higher serum concentrations of FSH (P < 0.01). No parameter correlated positively with ovarian response.