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B C Fauser

Publications and source records attributed to B C Fauser.

At least 73 records · Page 4Linked to original sources
PubMed1996

Serum and follicular fluid levels of insulin-like growth factor I (IGF-I), IGF-II, and IGF-binding protein-1 and -3 during the normal menstrual cycle.

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have important regulatory functions in ovarian follicular development. Although most studies have investigated the IGF system in ovarian cells in vitro, investigation of the IGF system in the peripheral circulation and in follicles of varying sizes throughout the menstrual cycle in large numbers of subjects has been lacking. In the current study we performed daily IGF-I, IGF-II, IGFBP-1, and IGFBP-3 measurements in 9 healthy regularly cycling volunteers throughout the menstrual cycle. In addition, we investigated IGF-I, IGF-II, IGFBP-1, and IGFBP-3 levels in 13 samples of androgen-dominant follicular fluid [FFa androstenedione to estradiol (AD:E2) ratio, > 4] and 19 samples of estrogen-dominant follicular fluid (FFe; AD:E2 ratio, 4) obtained from 21 regularly cycling subjects and in 18 samples of fluid from luteinizing follicles obtained from patients undergoing in vitro fertilization (IVF) treatment (FFivf). IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were measured using two-site immunoradiometric assays. No significant day to day differences were observed in IGF-I, IGF-II, IGFBP-1, and IGFBP-3 levels across the menstrual cycle. Median IGF-II levels in FFe (630 ng/mL; range, 212-1000) were significantly higher compared to those in FFa (474 ng/mL; range, 272-603; P = 0.002). Median IGFBP-3 levels in FFe (2955 ng/mL; range, 388-3448) were also significantly higher than those in FFa (2352 ng/mL; range, 756-2604; P = 0.003). Median IGF-I (192 ng/mL; range, 29-256) and IGFBP-1 (12 ng/mL; range, 2-281) levels in FFe were not significantly different from those in FFa [149 (range, 22-232) and 21 (range, 5-32) ng/mL, respectively). In contrast, significantly lower IGFBP-1 levels were found in FFe compared to FFivf (79 ng/mL; range, 57-234; P = 0.002), whereas there was no significant difference between FFe and FFivfe IGF-I, IGF-II, or IGFBP-3 levels, respectively. IGF-II levels were correlated with follicle diameter (r = 0.52; P = 0.002), cycle day (r = 0.47; P = 0.0065), E2 levels (r = 0.53; P = 0.003), AD:E2 ratio (r = -0.58; P = 0.001), and P concentrations (r = 0.60; P = 0.001) in all follicles, whereas no such correlations were found with IGF-I. In conclusion, as circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 are not menstrual cycle dependent, it is unlikely that these growth factors and these binding proteins play an endocrine role in cyclic ovarian follicle development, although both cycle-dependent delivery to the ovary and modification of their actions locally within the ovary cannot be excluded. With regard to FF1 the findings that IGF-II levels in FF1 are elevated compared to those in FFa and correlate with follicular functional status support a role for IGF-II during development of the dominant follicle. In addition, as IGFBP-3 in estrogen-dominant follicles mirrors the rise of IGF-II, this IGFBP may be a primary regulator of IGF-II action within the estrogen-dominant follicle. Finally, the finding of elevated levels of IGFBP-1 in luteinizing (IVF) follicles suggests an important role for this peptide in corpus luteum regulation.

Adult↗
PubMed1996

Application of a CHO cell line transfected with the human FSH receptor for the measurement of specific FSH receptor activation inhibitors in human serum.

Effects of FSH on ovarian follicular development can be modulated by factors present in serum or by locally produced factors in follicular fluid. Some of these factors may act directly on the FSH receptor. A Chinese hamster ovary cell line (CHO-F3B4) stably transfected with the human FSH receptor has been used to measure the effects of these modulators on FSH-stimulated adenylate cyclase activity. After incubation of CHO-F3B4 cells with human recombinant FSH (recFSH) for 4 h, cAMP levels were elevated 100-230 times above basal levels (ED50 24.9 mU/ml recFSH). cAMP production was inhibited after the addition of increasing amounts (up to 90% of the incubation volume) of hypogonadotrophic human serum (HS) at a fixed stimulatory dose of 30 mU/ml recFSH. At 10% HS the cAMP response was diminished to approximately 40-60% of the original value, whereas at a concentration of 90% HS the cAMP values were diminished to 30%. Effects of serum components on cell viability could be excluded, since forskolin- and cholera-toxin-stimulated cAMP production were not affected by preincubation of the cells in the presence of HS. The FSH-stimulated oestradiol production in rat Sertoli cells, which has been used frequently for in vitro bioassays of FSH, was almost completely inhibited by the addition of human serum, suggesting that serum has more pronounced effects on events downstream of receptor activation. Various specific FSH binding inhibitors have been demonstrated by radioreceptor assays to be present in serum. In order to assess whether such FSH receptor binding inhibitors would also inhibit receptor activation, the specific conditions used in the radioreceptor assays (buffers of low ionic strength) were also used to measure the effects of serum on FSH receptor activation. Under these conditions (a low-salt buffer, corrected for low osmolarity with 200 mM sucrose), CHO-F3B4 cells responded to FSH stimulation in a similar way to that observed in normal buffers. When CHO-F3B4 cells were incubated in this low-salt buffer with a fixed low dose of FSH (3 mU/ml), the addition of 3-90% (v/v) dialysed HS inhibited the FSH-stimulated cAMP accumulation to a similar extent to that in standard conditions. The observed inhibition of adenylate cyclase activation by the low-molecular-mass fraction (< 10 kDa) of HS could be attributed to the presence of salts in this fraction, since the addition of PBS in similar concentrations displayed an equal degree of inhibition. It is concluded that the inhibitory effects of serum on FSH-stimulated cAMP production in CHO-F3B4 cells are small, compared with the inhibition of aromatase induction in rat Sertoli cells. The strong inhibition of aromatase in rat Sertoli cells may result from the effects of serum acting on the FSH receptors as well as on other pathways not related to the FSH receptor. Therefore, measurement of aromatase in Sertoli cells is not suitable for the detection of inhibitors of FSH receptor activation. The CHO-F3B4 cells are useful for the measurement of whether inhibition of FSH receptor activation occurs in serum or follicular fluid from patients with disturbed follicle development.

Adenylyl Cyclases↗
PubMed1995

Circulating and ovarian IGF binding proteins: potential roles in normo-ovulatory cycles and in polycystic ovarian syndrome.

IGFs function as co-gonadotropins in the ovary, facilitating steroidogenesis and follicle growth. IGFBP-1 to -5 are expressed in human ovary and mostly inhibit IGF action in in vitro ovarian cell culture systems. In the clinical disorder of polycystic ovarian syndrome (PCOS), which is characterized by hyperandrogenemia, polycystic ovaries and anovulation, follicles have a higher androgen: estradiol (A : E2) content and growth is arrested at the small antral stage. In the PCOS follicle, follicle stimulating hormone (FSH) and IGF levels are in the physiologic range, and even in the face of abundant androstenedione (AD) substrate, aromatase activity and E2 production are low. When PCOS granulosa are removed from their ovarian environment, they respond normally or hyperrespond to FSH. It has been postulated that an inhibitor of IGF's synergistic actions with FSH on aromatase activity may be one (or more) of the IGFBPs, which contributes to the arrested state of follicular development commonly observed in this disorder. High levels of IGFBP-2 and IGFBP-4 are present in follicular fluid (FF) from androgen-dominant follicles (FFa) from normally cycling women and in women with PCOS. This is in marked contrast to the near absence of these IGFBPs in estrogen-dominant FF (FFe), determined by Western ligand blotting. Regulation of granulosa-derived IGFBPs is effected by gonadotropins and insulin-like peptides. In addition, an IGFBP-4 metallo-serine protease is present in FFe, but not in FFa in ovaries from normally cycling women and those with PCOS, although the IGFBP-4 protease is present in PCOS follicles hyperstimulated for in vitro fertilization. Recent studies demonstrate that IGF-II in FFe is higher than in FFa' whereas IGF-I, IGFBP-3 and IGFBP-1 levels do not differ, underscoring the importance of local IGF-II production by the granulosa and the importance of IGFBP-4 and IGFBP-2 in regulation of IGF-II action within the follicle during its developmental pathway as an E2- or A-dominant follicle. In the androgen-treated female-to-male transsexual (TSX) model for PCOS, IGF-I, IGF-II, IGFBP-3 and IGFBP-1 levels do not differ.

Female↗
PubMed1995

Initial estradiol response predicts outcome of exogenous gonadotropins using a step-down dose regimen for induction of ovulation in polycystic ovary syndrome.

OBJECTIVE: To study ovarian stimulation and response patterns during a gonadotropin step-down dose regimen for induction of ovulation by applying a decremental dose regimen in polycystic ovary syndrome (PCOS) patients. DESIGN: The present prospective study involves 28 infertile clomiphene citrate-resistant PCOS patients during gonadotropin-induced cycles using a modified step-down dose regimen (and adjuvant GnRH agonist medication). Applied gonadotropin doses included initial daily doses of 150 IU IM followed by two reducing steps (37.5 IU each) based on sonographic criteria to a final daily dose of 75 IU IM. SETTING: Anovulatory infertile women in an academic referral center. INTERVENTION: Daily blood withdrawal and transvaginal pelvic ultrasound. MAIN OUTCOME MEASURES: Serum FSH and E2 concentration and follicle growth were investigated daily during gonadotropin administration. RESULTS: An initial 2.1-fold increase in serum FSH levels was observed followed by a subsequent decrease of 10% (median) per day for 4 days. Growth of ovarian follicles was sustained and ovulation achieved (midluteal P, 11.7 +/- 1.3 ng/mL; conversion factor to SI unit, 3.180; mean +/- SD) in 22 patients. Major variability in day 3 E2 increase (range, 67 to 866 pg/mL; conversion factor to SI unit, 3.671)--not related to differences in FSH serum concentrations and without changes in follicle number and size--suggests differences in ovarian sensitivity for FSH stimulation. A strong correlation (r = 0.82) was found between day 3 E2 increase and the chance of ovulation. Moreover, E2 levels on the day of gonadotropin dose reduction predict (r = 0.68) chances of late follicular phase E2 levels exceeding 871 pg/mL (conversion factor to SI value, 3.671). CONCLUSIONS: These findings provide the endocrine basis for the concept of gonadotropin induction of ovulation using a step-down dose regimen. Initial E2 increase (before initiation of follicle growth) represent differences in ovarian sensitivity to gonadotropins and predict treatment outcome.

Buserelin↗
PubMed1995

Genetic basis of human reproductive endocrine disorders.

Disturbed human reproductive function may be caused by environmental and/or genetic factors. Much information related to single gene defects underlying reproductive failure has become available in recent years due to advances in molecular biology. In this review, techniques currently applied for deoxyribonucleic acid (DNA) analysis are addressed. We also highlight underlying molecular mechanisms and the corresponding clinical presentation of single gene defects affecting (i) the hypothalamic-pituitary-gonadal axis, resulting in disturbed gonadotrophin-releasing hormone (GnRH) neuron migration, or leading to defective gonadotrophins, gonadotrophin receptors and the Gs alpha protein; (ii) gonadal and adrenal steroid biosynthesis and (iii) steroid and insulin receptors. The potential genetic basis of polycystic ovary syndrome is also discussed. Although disease states caused by well-defined genetic abnormalities appear to represent only a small proportion of those found in the patient population, it should be considered that these affected individuals represent only the most severe cases in a wide spectrum of genetic abnormalities underlying disturbed fertility. Comprehension of these extreme cases will provide the basis for the elucidation of more common reproductive disorders as the result of subtle genetic changes or increased susceptibility to environmental factors.

Endocrine System Diseases↗
PubMed1995

Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients.

A total of 82 normogonadotrophic clomiphene-resistant anovulatory patients were treated with exogenous gonadotrophins according to a step-down dose regimen during 234 cycles. In 43 (18%) cycles co-treatment with gonadotrophin-releasing hormone analogues was applied. The initial dose was between 1.5 and 2.5 ampoules (75 IU follicle-stimulating hormone each) per day (dependent on body weight), and decreasing steps of 0.5 ampoules/day were based on sonographic findings. The overall ovulation rate was 91% (213 cycles). The median treatment period was 11 days and a total of 14 ampoules of gonadotrophin were needed. In 131 (62%) of the ovulatory cycles not more than one, and in 208 (98%) cycles not more than two, follicles > or = 16 mm were present on the day human chorionic gonadotrophin was given. A total of 37 pregnancies occurred of which two were twins and one was a triplet (multiple pregnancy rate 8%). The pregnancy rate per cycle was 17% and the cumulative pregnancy rate after 7 months was 47%. The abortion rate was 19%. There were four (1.7%) cases of mild ovarian hyperstimulation, of which none became pregnant. In conclusion, this study shows that the applied step-down regimen for gonadotrophin induction of ovulation can be a safe and effective treatment alternative for patients with clomiphene-resistant anovulation. The duration of ovarian stimulation and the amount of exogenous gonadotrophin required is limited. Pregnancy rates are comparable with those reported for step-up regimens, and a low incidence of complications (i.e. multiple gestation and ovarian hyperstimulation) was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Estrogen- but not androgen-dominant human ovarian follicular fluid contains an insulin-like growth factor binding protein-4 protease.

Estrogen-dominant follicular fluid (FFe) and granulosa-luteal cell conditioned media, in contrast to androgen-dominant FF (FFa), contain barely detectable levels of insulin-like growth factor binding protein-4 (IGFBP-4) by ligand binding techniques. The current study was designed to evaluate the possibility of an IGFBP-4 protease in FFe, which may alter the affinity of IGFBP-4 for insulin-like growth factors (IGFs), rendering IGFBP-4 undetectable by ligand binding techniques. FFe and FFa were obtained from regularly menstruating women, and FFe was also obtained during in vitro fertilization procedures. Mixing experiments were performed by using human recombinant IGFBP-4 or IGFBP-4 in nonpregnancy serum (NPS) as substrate and FF as the source of the putative protease. Incubation of NPS at 37C for 5 h in the presence of FFe resulted in the reduction of IGFBP-4 to barely detectable levels when analyzed by Western ligand blotting, with no change occurring in the levels of the other binding proteins present in NPS. In contrast, incubation of FFa with NPS under similar conditions had no effect on the levels of IGFBP-4. The disappearance of IGFBP-4 when NPS was mixed with FFe exhibited optimal pH-dependence at pH 7-9. Inhibition of the putative protease by aprotinin, ethylenediaminetetraacetic acid, and 1,10-phenanthroline supports its identification as a metalloserine protease. Western immunoblot analysis detected the presence of a proteolytic fragment of approximately 17-18 kDa after incubation of recombinant IGFBP-4 in the presence of FFe but not in the presence of FFa. Similar incubation of other recombinant human IGFBPs did not reveal their degradation, further suggesting that the protease in FFe is specific for IGFBP-4. These data demonstrate the presence of an IGFBP-4-specific metalloserine protease in FFe but not in FFa, and they suggest that proteolytic cleavage may be responsible for effectively decreasing levels of inhibitory IGFBP-4 and thus increasing bioavailability of IGF peptides within estrogen-dominant follicles. The importance of this mechanism may lie in providing the dominant follicle with more available IGFs to synergize with gonadotropins in stimulating estradiol production and in inhibiting this synergy in androgen-dominant and atretic follicles.

Androgens↗
PubMed1995

Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle.

OBJECTIVE: To study the relationship between decreasing serum FSH levels in the follicular phase of the normal menstrual cycle and follicle development by means of transvaginal sonography and E2 production. DESIGN: Daily blood samples were taken and transvaginal sonography was performed every other day in 16 normal regularly cycling female volunteers. MAIN OUTCOME MEASURE: Serum levels of FSH, LH, E2, and P and follicle diameter by transvaginal sonography. RESULTS: A distinct variability in individual maximal early follicular phase FSH plasma levels was observed (range 4.4 to 11.2 mIU/mL [conversion factor to SI unit, 1.000]). Differences in maximum FSH levels did not correlate with other endocrine or sonographic follicular phase characteristics. The follicular phase FSH decrease (from median 6.6 to 2.9 mIU/mL [conversion factor to SI unit, 1.000]) took place between cycle day 5 and 13 and was linear (0.5 +/- 0.05 mIU/mL per day; mean +/- SD). A significant correlation was found between serum FSH decrease and E2 increase. The day of sonographic appearance of a dominant follicle (median cycle day 8) did correlate with the first rise of the E2 plasma concentration. CONCLUSIONS: The present study suggests that even in women exhibiting normal ovarian function a 2.5-fold difference in FSH threshold concentrations for follicle recruitment does occur. Moreover, the magnitude of decrease in serum FSH concentrations during the follicular phase affects dominant follicle E2 production. The sonographic appearance of the dominant follicle is associated with a rise in serum E2 levels.

Adult↗
PubMed1994

First established pregnancy and birth after induction of ovulation with recombinant human follicle-stimulating hormone in polycystic ovary syndrome.

This case report describes the first established pregnancy and birth after induction of ovulation with recombinant human follicle-stimulating hormone (FSH) in a woman suffering from chronic clomiphene-resistant anovulation due to polycystic ovary syndrome (elevated serum luteinizing hormone and testosterone concentrations together with polycystic ovaries). Starting on day 3 of a progestagen withdrawal bleeding, 75 IU of rFSH was administered i.m. daily until a single preovulatory follicle was seen upon transvaginal ultrasound examination at day 13. Ovulation was induced by a single i.m. administration of 10,000 IU of human chorionic gonadotrophin, after which a viable singleton pregnancy was revealed at a gestational age of 6 weeks. The course of pregnancy and labour was uneventful and no abnormalities were found upon a paediatric examination.

Female↗
PubMed1994

Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women.

Seven women suffering from hypogonadism due to previous hypophysectomy, isolated gonadotrophin deficiency, or Kallman's syndrome [median age 39 years (range 24-45)] volunteered to participate in a study to assess ovarian response following multiple-dose administration of recombinant human follicle-stimulating hormone (rhFSH; Org 32489). Baseline serum FSH and luteinizing hormone (LH) concentrations were 0.25 (< 0.05-1.15) IU/l and 0.06 (< 0.05-0.37) IU/l, respectively. Subjects received daily i.m. injections of rhFSH for 3 weeks (week 1: 75 IU/day, week 2: 150 IU/day, week 3: 225 IU/day). Blood sampling and sonographic investigations were performed on alternate days. Steady-state FSH concentrations were reached approximately 3-5 days after alterations of the doses administered. Maximum FSH concentrations were between 7.1 and 11.8 IU/l, whereas serum LH concentrations remained unchanged. Due to absent follicle development and lack of a rise in immunoreactive inhibin (INH) (response failure possibly due to early ovarian failure or resistant ovary syndrome) in two subjects, analysis of ovarian response was restricted to five volunteers. Serum androstenedione levels showed no significant changes during rhFSH administration. Although serum immunoreactive INH concentrations reached normal late follicular values [659 (388-993) IU/l], serum oestradiol revealed only a minor increase [77 (18-210) pmol/l]. Moreover, growth of (multiple) ovarian follicles was observed up to pre-ovulatory sizes (> 15 mm) in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Observations in favor of normal early follicle development and disturbed dominant follicle selection in polycystic ovary syndrome.

Improved knowledge with regard to ovarian abnormalities in PCOS should help to classify patients suffering from this heterogeneous syndrome and may help to improve treatment outcome. Based on various observations, as previously discussed, it seems reasonable to assume that follicle development progresses to a size of 6-8 mm without an associated increase in estrogen biosynthesis. This is the size where dominant follicle selection takes place under normal conditions where follicle growth is arrested in polycystic ovaries. It may be hypothesized that under normal conditions FSH action is enhanced locally (for instance by changes in the IGF system) in the dominant follicle, whereas in polycystic ovaries this intraovarian upregulation is disrupted. Normal early antral follicle development is also confirmed by morphology studies. The classical concept of disturbed induction of the aromatase enzyme in PCOS should be questioned, since recent observations indicate that follicles may grow without a concomitant increased in intraovarian estrogens.

Cell Differentiation↗
PubMed1993

Insulin-like growth factor binding protein-2, 28 kDa and 24 kDa insulin-like growth factor binding protein levels are decreased in fluid of dominant follicles, obtained from normal and polycystic ovaries.

In order to investigate potential changes in insulin-like growth factor binding proteins (IGFBPs) during human follicle maturation, we examined the IGFBP profiles in follicular fluid from follicles in different stages of maturation. Samples were obtained from ovaries of women with regular menstrual cycles and of subjects with cycle abnormalities and polycystic ovaries (diagnosed as polycystic ovary syndrome (PCOS)) and analyzed by Western ligand blotting. IGFBPs of 43 kDa, 37 kDa, 31 kDa, a doublet around 28 kDa and a minor band of 24 kDa were detected in follicle fluid of normal non-dominant (size < 10 mm) and atretic (androstenedione/estradiol ratio > 4) follicles of both regularly menstruating women and PCOS patients. The 43 and 37 kDa IGFBPs could be identified as IGFBP-3 and the 31 kDa IGFBP as IGFBP-2, whereas the 28 kDa IGFBP could not be identified as IGFBP-1, all by immunoblotting techniques. A dramatic decrease in IGFBP-2, the 28 kDa and 24 kDa IGFBPs was observed in follicular fluid of dominant follicles (size > 10 mm) of both regular menstruating individuals and one PCOS patient as compared with follicular fluid of normal non-dominant or atretic follicles. These observations indicate that the PCOS follicle may not be different from normal with respect to IGFBP profiles. Furthermore, these results suggest that at least one of these IGFBPs might be involved in human folliculogenesis.

Adult↗
PubMed1993

Association between ovarian changes assessed by transvaginal sonography and clinical and endocrine signs of the polycystic ovary syndrome.

OBJECTIVE: To determine whether ovarian polycystic changes estimated by transvaginal sonography correlate with clinical and endocrine findings associated with the polycystic ovarian syndrome. DESIGN: Prospective study. SETTING: Reproductive Endocrinology Unit in the Department of Obstetrics and Gynecology at a teaching hospital. PARTICIPANTS: Ninety-five consecutive patients suffering from oligoamenorrhea entering an infertility treatment program. INTERVENTIONS: All women were examined by transvaginal sonography, assessed for body mass index and hirsutism. Blood withdrawal was performed for hormone estimates. MAIN OUTCOME MEASURES: Ovarian follicle number, volume, and stroma echogenicity. Estimates of immunoreactive and bioactive luteinizing hormone (LH), testosterone (T), free T, insulin levels, and insulin resistance index were performed. RESULTS: Hirsutism was present in 63% of the patients and correlated with the number of follicles, ovarian volume, and stroma echogenicity. Follicle number, ovarian volume, and stroma echogenicity values were significantly correlated with immunoreactive LH, bioactive LH, and T levels. Both T and immunoreactive LH were independently correlated with ovarian structure sonography parameters. Insulin and insulin resistance correlated with ovarian volume and stroma echogenicity. Insulin resistance was of significant additional predictive value of ovarian volume and amount of stroma. Evaluating the predictive value of immunoreactive LH and T together in regard to all sonography parameters, only T levels were statistically significant predictors of increase in follicle number, ovarian volume, and stroma amount. CONCLUSIONS: Although immunoreactive LH and bioactive LH correlated with all ovarian parameters, the effect of androgens on ovarian changes appeared to be independent from LH. This further substantiates the apparent cardinal role of androgens in the genesis of polycystic ovaries. Besides, transvaginal sonography assessment of ovaries is a valuable additional tool for the diagnosis of PCOS. In this regard, insulin resistance is of additional predictive value for ovarian volume and stroma echogenicity.

Adult↗
PubMed1993

Determinants of lumbar bone mineral density in normal weight, non-smoking women soon after menopause. A study using clinical data and quantitative computed tomography.

OBJECTIVES: Is there an influence of oral contraceptive use, parity and lactation on early postmenopausal bone mass? Is assessment of reproductive history, body weight in combination with biochemical markers of bone metabolism suitable to predict lumbar bone mass soon after menopause? STUDY DESIGN: A cross-sectional study in 94 healthy, normal weight, non-smoking women, 1-3 years after spontaneous menopause. Bone mineral density (BMD) of the lumbar spine was measured with single energy quantitative computed tomography. RESULTS: Multiple regression analysis showed that only total duration of lactation and alkaline phosphatase (AP) levels are independently related to trabecular BMD (P = 0.001 and P = 0.002 respectively). AP was also associated with cortical BMD (P = 0.003). Assessment of reproductive history, body mass index and biochemical markers of bone metabolism could only account for 17% of the variation of trabecular BMD observed in the study population. CONCLUSION: This study suggests that total duration of lactation rather than parity is associated with trabecular BMD of the spine. Clinical assessment of risk factors unsuccessfully predicts lumbar BMD in healthy, early postmenopausal women.

Biomarkers↗
PubMed1993

The step-down principle in gonadotrophin treatment and the role of GnRH analogues.

This chapter has focused on the step-down principle for gonadotrophin induction of ovulation in women suffering from clomiphene-resistant anovulation. The physiological rationale of this approach has been highlighted. Under normal conditions, FHS levels surpassing the FSH threshold initiate gonadotrophin-dependent growth of a cohort of follicles (this process is referred to as 'recruitment'). Due to negative feedback actions, the FSH levels decrease and FSH is above the threshold for only a limited number of days (the 'FSH window'). Around the mid-follicular phase, selection of a dominant follicle takes place; in addition to relatively low serum FSH concentrations, intraovarian regulation appears to be important for this process. In the conventional step-up or low dose step-up protocols for gonadotrophin induction of ovulation, administered doses are kept constant once an 'adequate' ovarian response is observed, resulting in high FSH serum levels in the late follicular phase and a broad FSH window. This contradicts normal circumstances and may give rise to unintended interference with the selection process by continuously stimulating follicles to enter the growing pool. This may result in multiple follicle development which, in turn, may be related to higher rates of multiple pregnancies and ovarian hyperstimulation. Potential mechanisms underlying arrested follicle maturation in PCOS are also discussed since they appear to be of relevance for the induction of ovulation. Disturbed selection can be overcome in the majority of cases by elevating the serum FSH concentrations through the administration of exogenous gonadotrophins to surpass the elevated FSH threshold in these patients. Data obtained by our group so far suggest that in PCOS patients treated with gonadotrophins in a step-down fashion, follicles continue to mature and can be stimulated to ovulation. Moreover, the number of functionally active medium-sized follicles seems to be reduced. If monofollicular development is observed in these patients, growth rates and oestrogen serum levels are indistinguishable from unstimulated normal development of the dominant follicle. In our initial series of over 200 cycles of gonadotrophin treatment according to the step-down principle in clomiphene-resistant anovulatory patients, 84% of cycles were ovulatory and pregnancy was achieved in 18% of the cycles (giving a cumulative pregnancy rate of 51%). Moreover, the overall complication rate appears to be low. The potential advantages and critical points of adjuvant treatment with GnRH analogues is also discussed. It has been clearly demonstrated that premature luteinization can be prevented effectively. Various other potential advantages of cotreatment seems to justify adjuvant medication with GnRH agonists.(ABSTRACT TRUNCATED AT 400 WORDS)

Anovulation↗
PubMed1993

Luteal function following ovulation induction in polycystic ovary syndrome patients using exogenous gonadotrophins in combination with a gonadotrophin-releasing hormone agonist.

The luteal phase was studied in 12 polycystic ovary syndrome (PCOS) patients following ovulation induction using exogenous gonadotrophins combined with a gonadotrophin-releasing hormone agonist (GnRH-a). Human menopausal gonadotrophin (HMG) was preceded by 3 weeks of treatment with GnRH-a (buserelin; 1200 micrograms/day intra-nasally) and administered in a step-down dose regimen starting with 225 IU/day i.m. GnRH-a was withheld the day before administration of human chorionic gonadotrophin (HCG; 10,000 IU i.m.). Blood sampling and ultrasound monitoring was performed every 2-3 days until menses. The luteal phase was significantly shorter in PCOS patients as compared to eight regularly cycling controls: 8.8 (3.3-11.4) days [median(range)] versus 12.8 (8.9-15.9) days (P = 0.01). Median peak values for progesterone did not show significant differences comparing both groups: 52.3 (17.1-510.3) nmol/l versus 43.0 (31.2-71.1) nmol/l, respectively (P = 0.8). The interval between the day of the progesterone peak and return to baseline was significantly shorter in the PCOS patients than in controls: 2.5 (0.3-4.9) days versus 4.2 (3.9-10.5) days (P < 0.005). Luteinizing hormone (LH) concentrations during the luteal phase as reflected by area under the curve were significantly lower in PCOS as compared to controls: 4.4 (1.6-21.0) IU/l x days and 49.0 (27.8-79.6) IU/l x days, respectively (P < 0.001). In conclusion, patients with PCOS may suffer from insufficient luteal phases after ovulation induction using HMG/HCG in combination with a GnRH-a. The corpus luteum apparently lacks the support of endogenous LH and may be stimulated only by the pre-ovulatory injection of HCG.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗