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PubMed1985

Alternative indications for pulsatile gonadotropin-releasing hormone therapy in infertile women.

Three groups of women with different types of ovulatory dysfunction who had failed to conceive on conventional therapy were treated with pulsatile gonadotropin-releasing hormone (GnRH). Group A consisted of nine patients with luteal phase defect; group B included four patients with apparently normal menstrual cycles but disordered folliculogenesis seen by serial ultrasound examinations; and group C consisted of eight patients who exhibited anovulation or irregular ovulation. GnRH was administered subcutaneously or intravenously in dosages varying from 5 micrograms to 20 micrograms, with pulse frequency of 2 to 3 hours in 53 cycles. Forty-one cycles were ovulatory. Four pregnancies resulted, one ending in miscarriage at 12 weeks' gestation. Our results indicate that GnRH may be used as an alternative to the prevalent therapeutic methods for ovulatory dysfunction. Only those women who had anovulation and abnormal basal levels of serum luteinizing hormone were resistant to GnRH therapy.

Adult↗

PubMed1986

Mild endometriosis and ovulatory dysfunction: effect of danazol treatment on success of ovulation induction.

The effectiveness of ovulation induction with clomiphene citrate or human menopausal gonadotropins was evaluated in 52 infertile women with stage I or stage II endometriosis and ovulatory dysfunction: anovulation or luteinized unruptured follicle (LUF) syndrome before (group I) and after (group II) danazol treatment. The incidence of anovulation and LUF in the endometriosis population was 9% and 34%, respectively. In group I, 10 of 36 patients (27.8%) conceived, with an average of 17.6 induction cycles per pregnancy. In group II, 21 of 30 patients (70%) conceived, with an average of 4.5 cycles per pregnancy (difference significant at P less than 0.001). There was no difference in the average number of ovulation induction cycles per patient between groups I and II (4.9 and 3.1, respectively). Of 14 patients who did not conceive in group I and crossed over to group II, 9 (64.3%) conceived (not different from group II). Spontaneous abortion rates were 20% in group I and 14% in group II. These results indicate that mild endometriosis may interfere with conception through mechanisms other than ovulatory dysfunction and that treatment with danazol appears to more than double the fertility rate.

Adult↗

PubMed1991

Laparoscopic cautery in the treatment of endometriosis-related infertility.

Life table analysis and the two-parameter exponential method have been applied to pregnancy rates in 72 patients undergoing laparoscopic cautery exclusively. Patients with male factor infertility were excluded. Estimated cure rates for patients with stage I and II disease were 98.2% and 76.6%, respectively (not significantly different). No significant difference was seen when anovulation complicated the endometriosis (68.6%). When greater than one infertility factor was present, a significant difference was observed (50.6%). Patients with stage I disease had an average fecundity of 10.30% with decreasing values observed in stage II (7.59%), anovulation (6.67%), and more than one infertility factor (3.33%). We conclude that laparoscopic cauterization is an effective mode of therapy for the treatment of stage I and II endometriosis associated with infertility.

Adult↗

PubMed1993

Pulsatile luteinizing hormone secretion pattern in hyperandrogenemic women.

OBJECTIVE: To elucidate changes in gonadotropin secretion pattern in patients with hyperandrogenemic chronic anovulation of various origins. DESIGN AND PARTICIPANTS: Hyperandrogenemic patients (n = 32), divided into subgroups according to certain clinical and biochemical criteria, and a control group (n = 9) of regularly cycling women with normal androgen and PRL levels were prospectively investigated. SETTING: Infertility and Biochemical Endocrinology Unit, Department of Obstetrics and Gynecology, University of Düsseldorf, Düsseldorf, Germany. MAIN OUTCOME MEASURES: Blood samples for radioimmunological analyses of gonadotropins and steroids were taken at 10-minute intervals for 12-hour sampling periods. In nonamenorrheic patients, investigations were performed on the 5th day of a cycle. Pulsatile LH and FSH data were analyzed by computerized peak identification programs. RESULTS: In hyperandrogenemic women, mean LH levels were higher than controls, the most elevated concentrations being observed in women with secondary amenorrhea (subgroup 5), in those selected for elevated mean LH levels (subgroup 3), and in those with elevated T and/or androstenedione (A) but normal DHEAS levels (subgroup 1). With the exception of patients with DHEAS elevations but normal T and A levels (subgroup 2), LH pulse frequency and amplitude were increased with most distinct effects occurring in subgroups 3 and 5. Highly elevated T and free T levels were observed in subgroup 5 and in overweight patients (subgroup 6). Estrone (E1) serum concentrations were highest in those subgroups (3 and 5) in which acceleration of LH pulse frequency and increments in LH pulse amplitude were most pronounced; these parameters correlated significantly with E1 levels. CONCLUSIONS: Changes in pulsatile LH release in patients with hyperandrogenemic chronic anovulation correlate primarily with elevated E1 levels, rather than with T or A serum concentrations.

Adolescent↗

PubMed2001

Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome.

OBJECTIVE: To assess the role of endometrial thickness on vaginal ultrasound assessment and menstrual history in predicting endometrial hyperplasia in women with polycystic ovary syndrome (PCOS) who presented with infertility due to anovulation. METHODS: This was a prospective study in a university referral-based fertility and endocrine clinic. Fifty-six women with PCOS presenting with infertility due to anovulation underwent both vaginal ultrasound assessments and endometrial biopsies. The main outcome measures were the predictive value of sonographic endometrial thickness (primary objective) and the menstrual history with other clinical characteristics (secondary objective) for proliferative endometrium and endometrial hyperplasia in logistic regression analysis. Their predictive value was further examined by receiver operating characteristic curve analysis. RESULTS: Thirty-six PCOS patients (64.3%) had proliferative endometrium and 20 (35.7%) had endometrial hyperplasia. Five of the latter (25%) had cytologic atypia. Endometrial thickness less than 7 mm or intermenstrual interval less than 3 months (corresponding to more than four menstrual periods yearly) was associated with proliferative endometrium only. The endometrial thickness correlated positively with endometrial hyperplasia (P =.018) and, together with the average intermenstrual interval, were significant predictors of endometrial hyperplasia (P <.001). CONCLUSION: These findings point to the usefulness of obtaining a detailed menstrual history in women with PCOS by identifying those at increased risk of endometrial hyperplasia and who require an endometrial biopsy. The endometrial thickness corroborates this clinical impression and is particularly useful when the menstrual history is uncertain. Endometrial hyperplasia in this population is effectively excluded when the endometrial thickness is less than 7 mm.

Adult↗

PubMed2000

Follicular dynamics in the polycystic ovary syndrome.

Anovulation in women with polycystic ovary syndrome (PCOS) is characterised by arrested growth of antral follicles. A relative lack of FSH may contribute to the persistence of anovulation but is unlikely, by itself, to be a major cause of it. Granulosa cells from anovulatory women with polycystic ovaries hypersecrete oestradiol, compared with size-matched follicles from normal ovaries or polycystic ovaries from ovulatory women. This phenomenon appears to reflect a condition of advanced maturation of medium-sized antral follicles. The underlying basis for the abnormalities in anovulatory PCOS remains uncertain, but it is possible that there are intrinsic differences in folliculogenesis between polycystic and normal ovaries which affect preantral as well as antral follicles. An alternative - but not mutually exclusive - explanation of this disorder is the abnormal endocrine environment. Hypersecretion of both LH and insulin are typical of anovulatory women with PCOS. Studies in isolated granulosa cells, have shown, that insulin greatly augments the action of LH on steroidogenesis but this interaction may compromise further growth of medium-sized antral follicles by generation of 'preovulatory' concentrations of cAMP within the granulosa cell and thereby leading, prematurely, to terminal differentiation of granulosa cells.

Anovulation↗

PubMed2004

Should insulin-sensitizing drugs be used in the treatment of polycystic ovary syndrome?

Insulin resistance is a central feature of polycystic ovary syndrome (PCOS). Hyperinsulinaemia contributes to anovulation, hyperandrogenism, infertility and early pregnancy loss in women with PCOS. Chronic hyperinsulinaemia also predisposes women with PCOS to increased risks of diabetes and cardiovascular events. Current data indicate that metformin, either as monotherapy or in combination with clomiphene in clomiphene-resistant patients, is an effective treatment for anovulation in PCOS. Initial evidence also suggests that insulin sensitizers may have a role in preventing early pregnancy loss. Of the available insulin-sensitizing agents, metformin has been the agent most frequently studied in PCOS, and has the least undesirable pregnancy safety profile. Ameliorating the metabolic syndrome associated with insulin resistance in PCOS with metformin may also prevent long-term cardiovascular and diabetes complications, pending further evidence. Based on these data, metformin should be a first-line therapy for women with PCOS.

Abortion, Spontaneous↗

PubMed1988

[Induction of follicle maturation with "pure" FSH in polycystic ovary syndrome].

The Polycystic Ovary Syndrome (PCO) is characterised by an elevated ratio of serum LH to FSH in presence of an intrafollicular deficiency of FSH activity. Ovulation induction by "pure" FSH seems therefore a reasonable approach to longstanding chronic anovulation in infertile patients suffering from PCO. 68 treatment cycles have been conducted in 30 patients with PCO and chronic clomiphene-resistant anovulation. Ovulation has been induced by HCG in 57 of the 68 cycles. The pregnancy rate was 58.6% per patient, the success rate 46.7% per patient. Clinical abortions occurred in 17.6% of the pregnancies obtained. 3 twins and 2 triplets have been delivered at term. A hyperstimulation syndrome (HSS) of grade I (WHO) has been observed in 19.1%, a HSS of grade II (WHO) in 8.8% of the treatment cycles. 46.3% of the 54 analysed cycles presented a premature LH-surge leading to an atresia of the dominant follicle. Considering the high incidence of a premature elevation of endogenous LH, an additional administration of exogenous LH should be avoided. This consideration as well as the good success rate in the present series speak in favour of using "pure" FSH for induction of follicular maturation in clomiphene-resistant PCO.

Adult↗

PubMed1989

[Preclinical hypothyroidism and disorders of ovarian function].

For sensitive assessment of thyroid function a TRH stimulation test using 200 micrograms TRH i.v. was routinely performed in 304 women admitted for evaluation and treatment of infertility. In 37 cases (12.2%) the reaction of TSH 30 min after injection of TRH i.v. was enhanced (by definition of a peak TSH level greater than 25 mIU/l), according to mild or subclinical hypothyroidism. Approximately 14 (14/37 = 37.8%) of these patients were found to have slightly elevated serum PRL values (mean PRL greater than 15 ng/ml). Cycle analysis by means of basal body temperature and evaluation of progesterone and oestradiol values, supplied evidence of luteal phase deficiency in 8 and anovulation in 3 cases. Another group of 11 patients with hypothyroidism involved oligo-/amenorrhoea, hirsutism and hyperandrogenaemia. After treatment with 50-150 micrograms l-thyroxine daily for at least 4 to 6 weeks, elevated PRL values significantly decreased (mean level less than 15 ng/ml, p less than 0.01) in 9 out of 12 patients and testosterone levels slightly decreased in 5 out of 8 patients. An improvement of the cyclical ovarian function could be observed by the significant increase of the average progesterone concentration in the luteal phase. During therapy with l-thyroxine, 4 pregnancies occurred. From these results we conclude, that mild hypothyroidism may cause ovarian insufficiency. Assessment of thyroid function should be mandatory in infertile patients with elevated prolactin levels or chronic anovulation.

Adult↗

PubMed1985

Evaluation of the anovulatory patient. When to proceed, when to refer.

The anovulatory patient presents the primary care physician with what is often a diagnostic and therapeutic challenge. To meet this challenge and avoid doing a disservice to the patient, the physician needs to have both a firm understanding of the disease process and an adequate understanding of available treatment methods. Anovulation must be considered before it can be recognized. Once it is suspected, a thorough yet judicious approach to diagnosis must be undertaken. In these days of diagnosis-related groups (DRGs) and prospective reimbursement, a thoughtful, logical, cost-effective approach to the diagnosis of anovulation is more critical than ever. Finally, once the diagnosis is achieved, investigation of the etiologic factor can proceed in an orderly, stepwise fashion. There is no place for a shotgun approach in the work-up of the anovulatory patient. Even more important to the primary care physician is a firm understanding of when to refer. While straightforward aspects of the patient evaluation are best accomplished at the local level (indeed, the tertiary care center could not and should not try to cope with total referral), complex diagnostic and therapeutic regimens should be handled by the reproductive endocrinologist. Patients with hyperprolactinemia, those who have failed ovulation induction with clomiphene citrate (Clomid), those with suspected outflow tract anomalies, and hypoestrogenic patients surely should be evaluated and treated in consultation with the specialist. This approach of careful, efficient initial assessment coupled with appropriate use of the reproductive endocrinologist and tertiary referral center leads to optimum care of the anovulatory patient.

Anovulation↗

PubMedDate not supplied

Advanced maternal age is not only associated with newborn somatometrics but also with the mode of delivery.

BACKGROUND: At both extremes of reproductive phase, female cycles are characterized by a high rate of anovulation, and pregnancies at these phases of reproductive span are considered as risky for obstetric complications, poor pregnancy outcome and increased maternal and newborn morbidity and mortality. AIM: To analyse if this high rate of anovulation may be interpreted as an adaptation to poor pregnancy outcome. Therefore the association patterns between maternal age and newborn somatometric characteristics and the mode of delivery were tested. SUBJECTS AND METHODS: The associations between the age as well as somatic characteristics such as pre-pregnancy weight, stature, pelvic dimensions and pregnancy weight gain of 10 765 women aged between 12 and 49 years (mean = 25.3, SD = 5.7) and newborn body dimensions and the mode of delivery were analysed. RESULTS: With increasing maternal age, maternal and newborn body dimensions increased significantly. Although extremely young mothers were significantly shorter and lighter and exhibited the significantly lowest pre-pregnancy weight status and the narrowest pelvic dimensions, they showed the lowest rates of caesarean sections (13.1%) and, unexpectedly, not the highest rate of low weight newborns (<2,500 g). In contrast, for mothers older than 35 years the highest rate of low weight newborns (3.7%) and the highest rate of macrosom newborns (<4,000 g) were found. Furthermore, mothers older than 40 years experienced the significantly highest rate of caesarean section (31.3%). CONCLUSIONS: Special risks were found for mothers older than 35 years, so the lower rates of ovulatory cycles during this phase of life may be interpreted as an adaptation to increased risks for complications and poor pregnancy outcome.

Adolescent↗

PubMed2005

Therapeutic strategies for ovulation induction in infertile women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hirsutism, obesity, hyperandrogenism and insulin resistance. The syndrome is often accompanied by infertility because of anovulation. Many approaches have been proposed to solve this problem, with the most commonly used therapies being ovarian drilling and pharmacological ovulation induction. Ovarian drilling is a procedure in which a laser fiber or electro-surgical needle punctures the ovary four to ten times. Side-effects are rare and often related to surgery itself. Pharmacological strategies include administration of metformin and insulin-sensitizing agents, clomiphene citrate (CC), gonadotropins and aromatase inhibitors. Metformin appears valuable in increasing ovulation rate, menstrual cyclicity and pregnancy rate. CC is an oral estrogen antagonist that raises circulating concentrations of follicle-stimulating hormone (FSH) and induces follicular growth in most women with PCOS and anovulation. Failure to respond is associated with high body mass index and high androgen levels. Aromatase inhibitors mimic the central reduction of negative feedback through which CC works. Ovulation induction with recombinant FSH has proved successful, but treatment requires skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome. The hypothetical deleterious effects of the high luteinizing hormone concentrations observed in PCOS patients seem to be related to the concomitant hyperinsulinemia (and/or insulin resistance). A thorough understanding of the syndrome and a careful assessment of each patient are the mainstays for choosing an appropriate treatment regimen.

Anovulation↗

PubMed2006

Prevalence and clinical predictors of endometrial hyperplasiain anovulatory women presenting with amenorrhea.

The aim of the present study was to determine the prevalence and clinical predictors of endometrial hyperplasia (EH) in amenorrheic women with anovulation. Fifty-seven women were enrolled in the study. Of these, 43 were diagnosed to have polycystic ovary syndrome (PCOS) and 14 to have idiopathic anovulation. All women received transvaginal sonography to assess endometrial thickness (ET), patterns and abnormalities. At the same time, an endometrial biopsy was taken using a Pipelle instrument. The women's age, body mass index (BMI) and waist-to-hip ratio (WHR) were 32.0+/-6.0 years, 27.3+/-6.5 kg/m(2) and 0.82+/-0.06 (mean+/-standard deviation), respectively. Twenty (35.1%) and 19 (33.3%) women were classified as obese by BMI and WHR, respectively. Hypertension was found in 17 (29.8%) women. The prevalence of EH was 45.6%. Most cases were simple EH, and only one (1.75%) was simple EH with atypia. EH prevalence was 48.8% and 35.7% in PCOS and idiopathic anovulatory women, respectively. Age, BMI, WHR and ET did not predict EH, whereas the endometrial hyperechogenic pattern was a clinical predictor of EH with borderline significance. In conclusion, this study demonstrated that almost half of the anovulatory women with amenorrhea had EH and no significant predictor was found. In view of these findings, an endometrial biopsy should be performed in all women with this disorder.

Adult↗

PubMed2006

Is metformin a primary ovulatory agent in patients with polycystic ovary syndrome?

Insulin resistance is an important pathophysiological feature of the polycystic ovary syndrome (PCOS). Insulin resistance and its compensatory hyperinsulinemia contribute to the anovulation, hyperandrogenism, infertility and early pregnancy loss suffered by women with PCOS. Current evidence supports the role of metformin in the treatment of anovulation in PCOS, both in monotherapy and concomitantly with clomiphene in clomiphene-resistant patients. In addition, novel evidence suggests that insulin sensitizers may also play a role in reducing the risk of early pregnancy loss. The insulin-sensitizing agents available commercially include metformin, rosiglitazone and pioglitazone. Compared with the thiozolidinediones, metformin is the agent that has been most frequently studied in PCOS, and has the most favorable pregnancy safety profile. In conclusion, there is strong evidence supporting the use of metformin as a primary ovulatory agent in women with PCOS.

Anovulation↗

PubMed1997

Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment.

Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate. Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive, expensive, and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome. We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone (an opioid receptor blocker) alone or naltrexone in combination with an antioestrogen. In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed. In conclusion, ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients. Compared to gonadotrophin induction of ovulation, this method is safe, simple and inexpensive.

Administration, Oral↗

PubMed1998

Polycystic ovary syndrome: anomalies in progesterone production.

The underlying cause of anovulation and miscarriage in polycystic ovary syndrome (PCOS) is unknown. Progesterone may play an important role in oocyte fertilization and embryo implantation. Therefore, in this study we analyse the endocrine function of luteinizing granulosa cells to synthesize progesterone in vivo and in vitro in PCOS and normal patients participating in an in-vitro fertilization programme. Human luteinizing granulosa cells were obtained from 10 patients with normal ovaries (controls) and 10 patients with PCOS by follicular aspiration of individual follicles of each patient and pooled in an attempt to obtain three groups: cells from follicle sizes < or =10,>10< or =15 and > or =16. Serum concentrations of oestradiol and progesterone on the day of human chorionic gonadotrophin (HCG) injection were significantly higher (P < 0.01 and P < 0.05) in PCOS patients than in controls. After HCG stimulation, in-vitro progesterone production was enhanced in granulosa cells of the control group and concentrations increased with follicular size as expected. However, the concentration of progesterone of PCOS patients did not increase with follicular size and there was a significant difference between normal and PCOS groups in follicles >10< or =15 mm (P < 0.05) and > or =16 mm (P < 0.01). Oestradiol production was increased in follicles > or =16 mm in both groups, although this did not reach significance. In summary, it seems that PCOS granulosa cells demonstrate an abnormal capacity to synthesize progesterone in vivo and in vitro. The understanding of granulosa cell function in PCOS may explain the anovulation and miscarriage that occurs in these patients.

Abortion, Spontaneous↗

PubMed1999

Adipocyte insulin action following ovulation in polycystic ovarian syndrome.

The role of anovulation and insulin resistance in the pathogenesis of polycystic ovarian syndrome (PCOS) remains to be determined. The aim of this study was to investigate whether the metabolic abnormality of insulin resistance in PCOS reflects, rather than causes, the ovarian dysfunction. Eight subjects with classical PCOS were studied on two occasions. Adipocyte insulin sensitivity together with hormonal and metabolic changes were investigated in patients with PCOS following prolonged amenorrhoea and then again in the early follicular phase after ovulation. Insulin receptor binding in amenorrhoeic subjects with PCOS was low at 0.78 +/- 0.08% and this increased to 1.18 +/- 0.19% after an ovulatory cycle (P < 0.05). Maximal insulin stimulated 3-O-methylglucose uptake was 0.70 +/- 0. 14 during amenorrhoea and increased to 1.08 +/- 0.25 pmol/10 cm(2) cell membrane (P < 0.05). Plasma testosterone fell (4.0 +/- 0.4 to 2. 3 +/- 0.2 nmol/l; P < 0.001), luteinizing hormone fell (17.6 +/- 2.3 to 6.7 +/- 0.8 IU/l; P < 0.001) but plasma insulin concentrations remained unchanged following ovulation (14.6 +/- 1.9 and 15.7 +/- 3. 8 pmol/l during amenorrhoea and after ovulation respectively). The results of this study suggest that chronic anovulation per se appears to modify the factors contributing to cellular insulin resistance seen in PCOS.

3-O-Methylglucose↗

PubMed1993

Pulsatile intravenous gonadotrophin releasing hormone for ovulation induction: determinants of follicular and luteal phase responses.

When anovulation results from a deficiency of gonadotrophin-releasing hormone (GrRH), substitution therapy with pulsatile peripheral i.v. GnRH is almost always successful. A review of published papers leads to the following conclusions for achieving the best results: (i) the i.v. route is superior to the s.c. route; (ii) the pulse interval should lie between 90 and 60 min, and may be shortened, but not lengthened, as follicular response takes place; (iii) the pulse dose for i.v. administration should be approximately 75 ng/kg (in practice, 2.5 micrograms/pulse for women weighing < 50 kg and 5.0 micrograms/pulse for women weighing > 50 kg is satisfactory). The more profound the degree of hypothalamic and pituitary suppression when GnRH is started, the longer the preliminary rise in FSH will last and the longer will be the duration of the follicular phase. The greater the tendency towards exaggerated LH release (indicating polycystic ovary syndrome), the less likely it is that satisfactory follicular development will follow. The luteal phase depends on (i) the adequacy of follicular development, (ii) the adequacy of the ovulatory stimulus, and (iii) continued trophic stimulus from LH or from administered human chorionic gonadotrophin. Ovulation rates with pulsatile GnRH in hypothalamic chronic anovulation should exceed 95% and appear limited only by technical failures.

Anovulation↗