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R Homburg

Publications and source records attributed to R Homburg.

At least 19 recordsLinked to original sources
PubMed2007

Why does ovarian surgery in PCOS help? Insight into the endocrine implications of ovarian surgery for ovulation induction in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex disorder with heterogeneity of clinical and endocrine features. Ovarian surgery for ovulation induction has been used in the management of clomiphene citrate-resistant anovulatory women with PCOS. Various types of ovarian surgery have been employed (wedge resection, electrocautery, laser vaporization, multiple ovarian biopsies and others) and all procedures result in an altered endocrine profile after surgery. The mechanism behind the reversal of endocrinological dysfunction in PCOS after ovarian surgery remains incompletely understood. This review scans the literature systematically to identify the endocrine changes after ovarian surgery in PCOS, in order to glean some knowledge of the mechanism involved. After ovarian surgery in PCOS, a rapid reduction in serum levels of all ovarian hormones is seen, in combination with increased serum levels of pituitary hormones. Folliculogenesis is then initiated and ovarian hormone production increases, synchronically with a reduction of pituitary hormones. Continuation of follicle growth in subsequent cycles after ovarian surgery occurs in an environment with less androgens and lower LH and FSH levels compared with pretreatment levels. The endocrine changes found after ovarian surgery in PCOS women seem to be governed by the ovaries themselves. Rapid reduced secretion of all ovarian hormones restores feedback to the hypothalamus and pituitary, resulting in appropriate gonadotrophin secretion. Initiation of follicular development seems to be induced by increasing FSH levels following a reduction of the follicle excess and (intra-ovarian) androgen levels. Additionally, anti-Müllerian hormone and gonadotrophin surge attenuating factor probably have a role in the endocrine changes.

Endocrine System↗
PubMed2006

Factors determining early pregnancy loss in singleton and multiple implantations.

BACKGROUND: The incidence of first trimester pregnancy loss is much lower in IVF twin pregnancies than in IVF singleton pregnancies. The objective of this study was to determine which embryonic and maternal factors contribute to this finding. METHODS: Retrospective data analysis of the outcome of 1593 pregnancies after day 3 double-embryo transfer (DET) after IVF or ICSI treatment. RESULTS: Of 1148 single implantations at 6 weeks, 936 (81.5%) were ongoing pregnancies. Of 445 multiple implantations at 6 weeks, 354 (79.6%) were ongoing multiple pregnancies, 80 (17.9%) were ongoing singleton pregnancies and 11 (2.5%) ended in a spontaneous abortion. Total pregnancy loss was 18.5 and 2.5% (P < 0.001) in singleton and twin gestations, respectively. Loss per gestational sac was 18.5 and 11.46% (P < 0.001), respectively. Determinants contributing to the continuation of gestation beyond 6 weeks were young maternal age, possibility to cryopreserve embryos and short GnRH agonist flare-up stimulation protocol. Whereas factors promoting multiple implantation at 6 weeks of gestation were young maternal age, high cumulative embryo score (CES), male infertility, long stimulation protocol and thick endometrium. CONCLUSIONS: Although multiple implantation at 6 weeks is predominantly determined by (morphological) embryo quality, the continuation of pregnancy beyond 6 weeks becomes more dependent on the combination of genetic and developmental potential of the embryo(s) and an optimal uterine milieu.

Abortion, Spontaneous↗
PubMed2006

The paradox of declining fertility but increasing twinning rates with advancing maternal age.

BACKGROUND: Advancing female age is associated with declining fertility potential due to decreasing numbers and quality of oocytes but also with a distinct increase in dizygotic twinning rates, a phenomenon that has never been explained. METHOD: An analysis of follicle development was made in 959 spontaneous ovulatory cycles of 507 women. RESULTS: Multiple ovarian follicular development (>1 follicle >14 mm) and, by implication, multiple rather than single ovulations occurred in 105 women whose mean age (36.1 versus 34.6 years) and mean basal FSH concentrations (10.3 versus 7.7 IU/l) were significantly greater than those with monofollicular development (P < 0.01). The prevalence of multifollicular development increased with age. CONCLUSIONS: Dizygotic twinning must be associated with the development of >1 large follicle, which we found to be a significantly more frequent occurrence in older women. It is hypothesized that the response of pituitary release of FSH to the decreased negative feedback induced by impending ovarian failure often 'overshoots', causing multiple follicular development. In the presence of two good-quality oocytes, a twin pregnancy may result.

Adult↗
PubMed2006

GnRH agonist versus GnRH antagonist in ovarian stimulation: is the emperor naked?

OBJECTIVE: The aim of the study was to evaluate the influence of type of GnRH-analog used during controlled ovarian hyperstimulation (COH) on the outcome of in vitro fertilization (IVF) cycles. PATIENTS AND METHODS: All consecutive women aged < or = 35 years admitted to our IVF unit from January 2001 to December 2004 were enrolled in the study. Only patients undergoing up to their third IVF cycle attempt were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryos transferred, and clinical pregnancy rate were compared between women given GnRH-agonist or GnRH-antagonist during COH. RESULTS: Four hundred and eighty-seven consecutive IVF cycles were evaluated, 226 in the agonist group and 261 in the antagonist group. A clinical pregnancy was achieved in 93 patients in the agonist group (pregnancy rate 41.2% per cycle) and 66 patients in the antagonist grup (pregnancy rate 25.3%); this difference was statistically significant (p < 0.01). The agonist group also used significantly more gonadotropin ampoules, required longer stimulation, and had higher estradiol levels on the day of human chorionic gonadotropin administration. CONCLUSION: The midluteal long GhRH-agonist suppressive protocol should be the protocol of choice in young patients in their first three IVF cycle attempts.

Adult↗
PubMed2005

The distribution of FSH receptor isoforms is related to basal FSH levels in subfertile women with normal menstrual cycles.

BACKGROUND: Recently a polymorphic variant of the FSH receptor in which amino acid asparagine (Asn) at position 680 is replaced by serine (Ser) was found. This is associated with higher FSH levels in the early follicular phase and an increased FSH requirement to obtain follicular response in IVF patients. The aim of our study was to test the hypothesis that this receptor isoform occurs more often in regularly menstruating subfertility patients with elevated basal FSH than in those with normal early follicular phase FSH. METHODS: A retrospective cohort study of 38 subfertility patients with a regular menstrual cycle and elevated FSH (>10 IU/l) compared to 40 patients with normal early follicular phase FSH was carried out. DNA was analysed to determine the FSH receptor genotype. RESULTS: The N680S variant on one or both alleles of the FSH receptor gene was significantly more prevalent in patients with elevated FSH (P < 0.05). The homozygous Asn/Asn variant at codon 680 was found in 45% of women with normal FSH and in 21% of women with elevated FSH. The homozygous Ser/Ser receptor variant was present in 12.5% of women with normal FSH and in 21% of patients with elevated FSH. Also the heterozygous combination of both variants Asn/Ser occurred more often in women with elevated FSH (58 versus 42.5%). CONCLUSIONS: The N680S sequence variation of the FSH receptor is found in >75% of the cases with elevated basal FSH and suggests a higher FSH threshold.

Adult↗
PubMed2005

Further considerations on natural or mild hyperstimulation cycles for intrauterine insemination treatment: effects on pregnancy and multiple pregnancy rates.

BACKGROUND: The high iatrogenic multiple pregnancy rate associated with intrauterine insemination (IUI) in hyperstimulated cycles is becoming less acceptable. Therefore we investigated data from an earlier prospective trial with regard to the specific question of whether the application of mild hyperstimulation in IUI cycles could be an alternative strategy for obtaining acceptable pregnancy rates while preventing a high multiple pregnancy rate, compared with natural cycles for IUI. METHODS: Pregnancy outcome of 310 natural and 334 mildly hyperstimulated cycles for IUI in 171 couples with unexplained or mild male factor subfertility was analysed on a patient level with random coefficient models. RESULTS: Pregnancy rates were similar: 35 and 39.8% per couple in the natural and mildly hyperstimulated cycles respectively (P = 0.60). Multiple pregnancies, all twin pregnancies, were conceived significantly more frequently in the mild hyperstimulation group (27% of the pregnancies) than in the natural cycle group (4% of the pregnancies) (P = 0.01). All multiple pregnancies in the hyperstimulation group were conceived in multifollicular cycles. Multifollicular development was strongly associated with the application of mild hyperstimulation only (odds ratio 21.14, 95% confidence interval 8.15-54.79). CONCLUSION: The application of a mild hyperstimulation protocol as an alternative to a standard hyperstimulation protocol for IUI does not result in higher pregnancy rates than IUI in the natural cycle, while at the same time multiple pregnancies cannot be avoided. Therefore, there is no place for the use of gonadotrophins in IUI treatment.

Adult↗
PubMed2005

Ovarian response to standard gonadotrophin stimulation for IVF is decreased not only in older but also in younger women in couples with idiopathic and male subfertility.

BACKGROUND: With the occasional reports of unexpectedly poor ovarian response to controlled ovarian hyperstimulation (COH) for IVF in young normally cyclic women in mind, we studied age-related ovarian response to COH in a group of women who underwent standard IVF. METHODS: Ovarian response to COH was defined as the number of follicles > or = 14 mm on the day of hCG administration. Ovarian response to COH was analysed by multiple regression analysis with woman's age and basal FSH concentration as explanatory variables in a prospective cohort of patients with idiopathic and mild male factor subfertility (n = 85), and additionally in a large retrospective cohort of women with unexplained, mild male and tubal subfertility (n = 1155), with age as explanatory variable. RESULTS: Ovarian response to COH was associated significantly with age (P < 0.001) and basal FSH concentration (P = 0.002). However, in women with idiopathic or mild male subfertility, in both cohorts the relationship took the form of an inverted U-shape with both older and--surprisingly--young women having a reduced ovarian response (P < 0.001). Maximum ovarian response was around the age of 28 years. In women with tubal infertility, there was only a linear decline of ovarian response with age. CONCLUSION: It is hypothesized that diminished ovarian response to COH in IVF is the very first sign of ovarian ageing in young women diagnosed with idiopathic and mild male subfertility.

Adult↗
PubMed2005

Polycystic ovary syndrome in adolescence. New insights in pathophysiology and treatment.

Polycystic ovary syndrome (PCOS) is a prevalent cause of menstrual disorders, acne and hirsutism presenting during adolescence. In the majority of cases, a familial trait is obvious but the offending genes have yet to be identified. However, much of the pathophysiology of the syndrome causing the overproduction of ovarian androgens is now becoming clearer. The early diagnostic signs are often mistakenly dismissed as normal changes of adolescence but it is important to make an early diagnosis in order to save the adolescent from the early and late stigmata of the syndrome. The avoidance of overweight, frank obesity and the consequential exaggeration of symptoms by the associated insulin resistance is of prime importance as hyperinsulinemia plays a key role in the pathogenesis. Anti-androgens are the most widely used medication and, in combination with estrogen, are capable of restoring menstrual regularity and reducing the symptoms of acne and hirsutism, so important for the improvement of the disturbing psychosocial effect that they may play at this age. The use of metformin, an insulin sensitizer, for affected adolescents is the topic of a presently heated debate.

Adolescent↗
PubMed2004

Assessment of ovarian reserve. Ovarian biopsy is not a valid method for the prediction of ovarian reserve.

The evaluation of ovarian reserve, often critical for the elderly infertile woman, is notoriously difficult and inaccurate. The place of ovarian biopsy in this evaluation has been hotly disputed for three decades, but not resolved. To examine the feasibility of ovarian biopsy for this purpose, a project was designed to estimate the total number of oocytes in a human ovary and investigate whether any biopsy regimen is representative of the follicular reserve in an individual. Ovaries removed from patients of reproductive age during operations not involving ovarian pathology were utilized to count the number and type of follicles found in multiple biopsies of 2 and 5 mm and in the whole ovary. Representative results taking into account the total number of follicles found in the whole ovary showed that predicted values based on the biopsies were extremely varied. We concluded that due to the huge variation in the distribution of follicles across the surface of the ovary, there is no place for this procedure in clinical evaluation of reproductive ageing in the individual patient.

Adult↗
PubMed2004

Induction of polycystic ovary by testosterone in immature female rats: Modulation of apoptosis and attenuation of glucose/insulin ratio.

Polycystic ovarian syndrome is seen in 5% of fertile aged women. However, there is no satisfactory PCOS model in experimental animals. To induce polycystic ovary phenotype in immature female rats, Wistar rats 21 days of age were injected daily with testosterone propionate 1 mg/100 g body weight dissolved in propylene glycol or propylene glycol for up to 35 days. Seven days of injection with testosterone (T) resulted in the appearance of large cystic follicles and a dramatic accumulation of multi-layer preantral follicles. At 42 days of age puberty in control animals was evident by the appearance of corpora lutea. In contrast in T treated animals no corpora lutea formation was seen even at the age of 56 days. Progesterone in the control animals was elevated at the age of 42 days in contrast with the T treated animals in which progesterone remained low (20% of control). While during 14 days of T injection most of the follicles did not have progressive apoptosis, at 21-35 days of injection (42-56 days of age) the vast majority of follicles became apoptotic. Progressive degeneration of oocytes was evident in T treated animals reaching 70-85% of total oocytes at 21-35 days of T injection compared to 30-40% in control animals. Western blot analysis of ovarian homogenates revealed gradual decrease in Bcl-2 content, evident at 28 and 35 days of T injection compared to control animals. Interestingly, the fasting glucose/insulin ratio was dramatically reduced in T treated animals following 14 days of testosterone treatment compared to controls. Our data suggest that T injection to immature female rats can induce polycystic ovaries, block ovulation and attenuate progesterone production. Moreover, normal/low glucose and high insulin blood levels in the testosterone treated rats raises the possibility that elevated androgens can lead to insulin resistance in this experimental PCOS model.

Animals↗
PubMed2001

Leptin attenuates follicular apoptosis and accelerates the onset of puberty in immature rats.

Human and rat granulosa cells express receptors to leptin which synergies with glucocorticoid hormones in stimulation of ovarian steroidogenesis. To examine whether leptin affects follicular development and maturation, we injected recombinant ovine leptin (300 ng-10 microg/animal) daily to immature 21 day-old female rats. Non-treated rats reached puberty at 44.5+/-1.6 (n=9) days. In contrast, in leptin treated animals, puberty was reached at 34.5+/-1.6 (n=9) days. Ovarian sections revealed hypertrophy of granulosa cells in leptin treated animals. Moreover, the number of ovulations was 2-fold higher in the treated animals compared to controls (3-4 ovulations versus 7-8 on the first three estrous cycles, P<0.001). Leptin dramatically reduced incidence of follicular apoptosis measured by TUNEL, and was already evident after 7 days of leptin injection (12% of apoptosis in leptin treated group compared to 52% in controls, P<0.001). Maximal protection against apoptosis was achieved at 1-3 microg leptin/animal. The levels of FSH, LH, progesterone and the steroidogenic factors ADX and STAR were elevated earlier in development in the leptin treated animals compared to control animals which is in line with the achievement of early puberty in the leptin treated animals compared to non treated ones. To reveal whether modulation of death and survival genes is involved in leptin attenuation of follicular apoptosis, we examined the expression of the survival gene Bcl-2 and the death gene Bax in Western blots of ovarian homogenates. There was a pronounced elevation in Bcl-2 expression during 7-14 days of leptin injections up to 16.3-fold (P<0.001) compared to Bcl-2 expression in controls. Bax expression was elevated only 3.4 fold (P<0.001), leading to an increase in the Bcl-2/Bax ratio of 4.7 fold (P<0.001). Expression of the tumor suppressor gene p 53 and the oncogene Mdm2 did not change significantly. Our data suggests that leptin may be involved in accelerating follicular maturation by attenuating follicular atresia and increasing the ratio of Bcl-2/Bax.

Adrenodoxin↗
PubMed2001

Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome.

BACKGROUND: Activin promotes ovarian follicular development, inhibits androgen production and increases FSH and insulin secretion. Follistatin, an activin-binding protein, neutralizes activin bioactivity. Therefore, a decrease in the ratio of activin/follistatin might encourage characteristic features of polycystic ovary syndrome (PCOS). We investigated whether women with PCOS showed disordered follistatin and/or activin serum concentrations. METHODS: The study group included 24 obese and 20 non-obese (body mass index vertical line and <27 kg/m2 respectively) clomiphene-failure PCOS patients. The control group included 16 obese and 46 non-obese patients with normal ovulatory cycles. Blood samples were obtained from the patients on day 3-5 of a progesterone-induced or spontaneous cycle and were assayed for LH, FSH, testosterone, 17-hydroxy-progesterone, androstenedione, follistatin, activin A, fasting glucose and insulin. RESULTS: Follistatin concentrations were comparable between obese and non-obese PCOS patients (mean +/- SE; 1171 +/- 103 and 1045 +/- 159 pg/ml respectively) and significantly higher than their respective controls (628 +/- 61 and 592 +/- 49 pg/ml, P < 0.0001 and P < 0.02 respectively). Activin A concentrations were comparable between the four groups (590 +/- 35, 513 +/- 74, 661 +/- 87 and 595 +/- 43 pg/ml in obese and non-obese PCOS and controls respectively). Stepwise regression analyses for relationships between follistatin or activin A levels and all other variables indicated that follistatin was significantly and independently positively affected by PCOS (P < 0.0001), age (P < 0.02), androstenedione (P < 0.03) and weight (P < 0.05). Activin A was significantly and independently negatively affected by PCOS (P < 0.003) and FSH (P < 0.03), and positively affected by weight (P < 0.009) and androstenedione (P < 0.02). CONCLUSIONS: Serum follistatin is increased in PCOS patients, regardless of obesity. PCOS is the most significant variable that relates to high follistatin and low activin A serum concentration. A high follistatin/activin ratio could well contribute to the pathophysiology of PCOS.

17-alpha-Hydroxyprogesterone↗
PubMed1999

Pharmacokinetics of natural progesterone administered in the form of a vaginal tablet.

Our study was conducted to assess the pharmacokinetics of natural progesterone administered in the novel formula of an effervescent vaginal tablet. Fifty post-menopausal women, with a median age of 43.5 years (range 28-55), volunteered to participate in the research. All women discontinued their hormonal replacement therapy 1 month prior to the study. The pharmacokinetics of 50 and 100 mg of progesterone administered as a vaginal tablet were evaluated. After the initial administration of 50 mg or 100 mg, a mean serum Cmax of 20.43 +/- 8.01 nmol/l and 31.61 +/- 12.62 nmol/l (P < 0.0004) was reached at a Tmax of 6.1 +/- 2.63 and 6.4 +/- 3.35 h respectively. The terminal half-life was 13.18 +/- 1.3 and 13.7 +/- 1.05 h respectively. Continuous use of the 100-mg tablet resulted in a mean serum progesterone concentration of 26.08 +/- 13.96 nmol/l and 21.42 +/- 16.32 nmol/l after 14 and 30 days respectively. Women >40 years were found to have a significantly lower Tmax compared to younger women (P = 0.02). The continuous use of vaginal progesterone did not influence the hormonal, liver or lipid profiles evaluated. Only three (6%) women suffered from mild vaginal irritation. Natural progesterone given as a vaginal tablet is well tolerated, safe and an easily administered treatment. Even in a non-oestrogenized vagina the absorption was efficient and the 100 mg dosage resulted in adequate serum progesterone concentrations.

Absorption↗
PubMed1998

Polysystic ovary syndrome--loss of the apoptotic mechanism in the ovarian follicles?

Polycystic ovary syndrome (PCOS) is the most prevalent female endocrinopathy and the largest single cause of anovulatory infertility. The PCOS is characterized by multiple small antral follicles arrested in their development but nonatretic and viable. The hyperexpression of some growth factors (e.g. EGF/TGF alpha) in PCOS, considered to be survival or antiapoptotic factors, led to the hypothesis of their involvement in the blocking of apoptosis and atresia leading to an accumulation of multiple small antral follicles. Diminished FSH stimulation and accumulation of androgens could explain the arrest of progress to the preovulatory stage. Further investigation of the pathogenesis of PCOS is needed on the modulation of tumour suppressor and apoptosis genes such as p53, BAX or the APO/FAS system and the over expression of survival genes such as BCL2.

Apoptosis↗
PubMed1998

Adverse effects of luteinizing hormone on fertility: fact or fantasy.

High tonic serum concentrations of luteinizing hormone (LH) in the follicular phase, frequently witnessed in polycystic ovary syndrome, have been associated with decreased reproductive function. Impaired rates of fertilization, conception and miscarriage are obtained when LH levels are high before oocytes are collected, during ovulation induction or in women with regular cycles. Conversely, treatment that decreases LH concentrations, such as gonadotrophin-releasing hormone analogue or laparoscopic ovarian puncture, eases induction of ovulation and pregnancy and improves miscarriage rates. Tonic hypersecretion of LH appears to induce premature oocyte maturation, causing the problems with fertilization and miscarriage.

Abortion, Spontaneous↗
PubMed1998

Uterine leiomyomata--a feature of acromegaly.

In order to assess the prevalence of leiomyomata in patients diagnosed with acromegaly, files of all women so diagnosed were obtained (n = 25). Eight of these patients had undergone hysterectomy. In eight of the remaining patients, assessment of the uterus was performed by gynaecological examination and transvaginal ultrasound. The prevalence of leiomyomata was 81% (13/16) in patients who had undergone hysterectomy (8/8) or who underwent gynaecological examination (5/8). In conclusion, the very high prevalence of leiomyomata in patients diagnosed with acromegaly warrants the inclusion of growth hormone excess as a cause of leiomyomata. Leiomyomata are a feature of the organomegalic syndrome associated with acromegaly.

Acromegaly↗
PubMed1998

Involvement of growth factors in the pathophysiology of polycystic ovary syndrome.

The etiology of polycystic ovary syndrome (PCOS) has not yet been fully elucidated but involves a disruption of normal ovarian function and multisystem sequelae. A combination of abnormally functioning genes whose expression is influenced by environmental, extra-ovarian factors determines the symptoms. Growth factors are heavily involved in the pathophysiology, either contributing to or as a consequence of the arrested development of follicles, abnormal steroidogenesis and hyperinsulinemia. Hyperactivity of a--transforming growth factor (TGFa) and epidermal growth factor (EGF) may block stimulation of aromatase and attenuate apoptosis of follicles and other factors may interface with the insulin-like growth factor (IGF) system preventing arrested follicles from becoming atretic and preventing the selection of a dominant follicle. IGF-binding protein concentrations are decreased by insulin, freeing biologically active IGF-I which augments the action of luteinizing hormone (LH) by inducing LH receptors, hyperactivating the enzymes P450c17a and 17,20 lyase resulting in hyperandrogenism. Growth hormone itself may be involved in the pathophysiology, as in normoinsulinemic PCOS patients it is hypersecreted and its actions on growth factors and their binding proteins are similar to those of insulin.

Androgens↗