The association between hyperandrogenemia and the metabolic syndrome in morbidly obese women.

BACKGROUND: Female abdominal obesity is associated with hyperandrogenemia (HA), but few studies have addressed the possible association between HA and metabolic syndrome (MetS) among obese women. Some studies indicate that insulin resistance may cause HA through different mechanisms. On the other hand, a bidirectional relationship between HA and insulin resistance has been suggested. Thus, we aimed to investigate if morbidly obese women with HA had higher odds of MetS and its components than those without HA (controls), independent of polycystic ovarian syndrome (PCOS) status. METHODS: This cross-sectional study comprised 1900 consecutive treatment seeking morbidly obese women <50 years. Free testosterone index (FTI) >0.6 defined HA. Women with previously diagnosed PCOS and those with oligo- / anovulation combined with clinical or biochemical hyperandrogenism were defined as having PCOS. Multiadjusted associations between HA and MetS were assessed by logistic regression analysis. RESULTS: Out of 1900 morbidly obese women, 1089 (57 %), 846 (45 %) and 312 (16 %) had MetS, HA and PCOS, respectively. Compared with controls (without HA), women with HA were younger (34 [1] years vs. 39 [2], p < 0.001) had a higher prevalence of MetS (62 % vs. 53 %, p < 0.001), type 2 diabetes (18 % vs. 15 %, p = 0.045), low HDL-cholesterol (65 % vs. 48 %, p < 0.001) and hypertriglyceridemia (48 % vs. 41 %, p = 0.004), but a lower prevalence of raised blood pressure (53 % vs. 59 %, p = 0.014). Multivariable analyses showed that HA was associated with increased odds of MetS (OR 1.61 [95 % CI 1.27, 2.02]), dysglycemia (1.65 [1.28, 2.11]), low HDL-cholesterol (1.58 [1.27, 1.97]), and hypertriglyceridemia (1.43 [1.15, 1.79]). After stratification for the presence of PCOS, the results remained largely unchanged in women without PCOS; MetS (1.52 [1.18, 1.96), dysglycemia (1.71 [1.30, 2.25]), low HDL-cholesterol (1.55 [1.22, 1.98]) and hypertriglyceridemia (1.36 [1.06, 1.74]). CONCLUSION: Morbidly obese women with HA had an approximately 1.5-fold increased odds of having MetS even in the absence of PCOS. Randomized controlled clinical trials, including therapeutic strategies to lower free testosterone levels, are however necessary to explore any cause-and-effect relationship.

Altered ovarian function and cardiovascular risk factors in valproate-treated women.

PURPOSE: Polycystic ovaries and menstrual disturbances seem to be common among women taking valproate for epilepsy. The purpose of the present study was to assess the frequency of valproate-related metabolic and endocrine disorders in different groups of women with epilepsy. SUBJECTS AND METHODS: Seventy-two women with epilepsy and 52 control subjects from centers in three European countries (Finland, Norway, and the Netherlands) participated in the study. Thirty-seven of the women with epilepsy were taking valproate monotherapy and 35 carbamazepine monotherapy. RESULTS: The frequency of polycystic ovaries or hyperandrogenism, or both, among valproate-treated women with epilepsy was 70% (26 of 37) compared with 19% (10 of 52) among control subjects (P <0.001). They were found in 79% (11 of 14) of obese and 65% (15 of 23) of lean women on valproate, and in 20% (7 of 35) of carbamazepine-treated women. The obese valproate-treated women with polycystic ovaries or hyperandrogenism, or both, had hyperinsulinemia and associated unfavorable changes in serum lipid levels consistent with insulin resistance. CONCLUSIONS: Polycystic ovaries and related hyperandrogenism are frequently encountered in both obese and lean women taking valproate for epilepsy. The use of valproate is associated with risk factors for cardiovascular disease in obese women.

Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome.

In overweight women with polycystic ovary syndrome (PCOS), increased insulin resistance has been observed. Since abdominal obesity is associated with impaired fibrinolytic capacity and elevated levels of plasminogen activator inhibitor (PAI-1) and since PAI-1 seems to be related to insulin resistance, we investigated the possible effects of dietary intervention on lipids, fibrinolysis, coagulation, and insulin sensitivity in obese PCOS women. Nine women aged 22 to 39 years (median weight, 97 kg) ate a protein-rich very-low-calorie diet (VLCD) (Nutrilett, Nycomed Pharma, Oslo, Norway; 421 kcal/d) for 4 weeks (part 1). After significant reductions of body fat (13%, P < .01), two of nine women achieved regular menstruation and became pregnant. Six of the remaining women continued on a conventional low-calorie diet (1,000 to 1,500 kcal/d) for the next 20 weeks (part 2), during which time they were generally able to preserve the body fat loss obtained in part 1 of the study. During part 1, significant reductions of total serum cholesterol (29%, P = .001) and fasting triglyceride ([TG] 31%, P < .05) levels were observed, as well as significant reductions of fasting glucose (6%, P < .05) and insulin (20%, P < .05). Insulin sensitivity (glucose disposal rate [GDR]) was increased by 93% (P < .05). After finishing part 2, insulin sensitivity was still significantly increased (86%, P < .05) and PAI-1 activity was significantly reduced (54%, P < .05). Moreover, overall fibrinolytic activity was significantly improved (serum D-dimer concentration increased by 75%, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Obstetric outcome in singleton pregnancies after assisted reproduction.

OBJECTIVE: To compare the obstetric outcome of singleton pregnancies after various procedures of assisted reproduction with a control group. METHODS: Maternal and perinatal outcome in 355 assisted-reproduction singleton pregnancies (study group) with a duration of 140 days or more were compared retrospectively with a control group matched for age and parity. All assisted-reproduction pregnancies resulted from treatment in one university hospital, and all control subjects delivered in the obstetric department of the same hospital. The controls consisted of 643 women, also with singleton pregnancies, who were matched for age and parity. RESULTS: In the study group, the frequencies of pregnancy-induced hypertension and placenta previa were increased. More patients in the study group were delivered by elective cesarean. Pregnancies after assisted reproduction were of shorter duration, with an increased incidence of preterm birth. Infants in the study group had a lower mean birth weight than did those in the control group and were more frequently referred to a neonatal care unit. CONCLUSION: Singleton pregnancies resulting from assisted reproduction represent obstetric risk cases, and the patients should be offered special attention during the pregnancy, which will probably be their only one.

Pregnancy after transfer of cryopreserved embryos in clomiphene citrate resistant polycystic ovarian syndrome.

Transfer of cryopreserved embryos in PCOS patients resistant to CC stimulation is an intriguing problem. Ovarian stimulation with hMG/hCG to create a secretory endometrium, will entail an unnecessary risk of OHSS. In this case study, we report the accomplishment of a successful pregnancy after transfer of cryopreserved embryos after secretory transformation of the endometrium by E2/P substitution in the absence of corpus luteum formation. However, the success rate of this treatment modality in terms of pregnancy per embryo transfer has still to be evaluated in an ongoing study.

Body weight, hyperinsulinemia, and gonadotropin levels in the polycystic ovarian syndrome: evidence of two distinct populations.

OBJECTIVE: To investigate the impact of body weight (BW) and insulin levels on gonadotropin and androgen levels in women with the polycystic ovarian syndrome (PCOS). DESIGN: Comparative study of endocrinologic parameters in PCOS women. SETTING: University Hospital Reproductive Endocrinology Unit. PATIENTS: Thirty obese and 19 nonobese women with PCOS. Seven obese and 7 nonobese normal women. MAIN OUTCOME MEASURES: Serum concentrations of insulin, testosterone, androstenedione, luteinizing hormone (LH), follicle-stimulating hormone. Serum LH response to gonadotropin-releasing hormone (GnRH) administration and assessment of insulin resistance by the continuous infusion of glucose with model assessment (CIGMA) test. RESULTS: Fasting insulin levels correlated with body mass index (BMI). Basal LH levels correlated inversely with BMI. Nonobese women with PCOS had a higher LH response to GnRH than obese women with PCOS. Only obese women with PCOS showed insulin resistance and fasting hyperinsulinemia. CONCLUSIONS: The data suggest that women with PCOS may be divided into two subgroups: those with obesity, insulin resistance, hyperinsulinemia, and normal/minimally elevated LH levels and those with normal BW, elevated LH levels, and normoinsulinemia.

Prediction of response to controlled ovarian hyperstimulation: a comparison of basal and clomiphene citrate-stimulated follicle-stimulating hormone levels.

OBJECTIVE: To test the ovarian reserve in a high-risk population before controlled ovarian hyperstimulation for in vitro fertilization (IVF). DESIGN: A prospective study comparing the outcome of a clomiphene citrate (CC) challenge test to the outcome of subsequent IVF cycles. SETTING: Unit for assisted reproductive technology in a university hospital. PATIENTS, PARTICIPANTS: Ninety-one infertile women with an age of 35 years or more, who had previous ovarian surgery or who had been diagnosed with ovarian endometriosis. MAIN OUTCOME MEASURE: Relate follicle-stimulating hormone (FSH) levels before and after CC to frequency of cancellation of an IVF cycle because of a poor follicular response. RESULTS: Twenty-one patients had elevated basal levels of FSH. Thirty-seven patients, including 20 with high basal levels, showed an excessive FSH response to CC with an FSH level after CC above the 95% confidence limit. Clomiphene citrate-stimulated FSH levels correlated better than basal levels with response to controlled ovarian hyperstimulation. An excessive FSH response to CC predicted a poor response outcome of subsequent controlled ovarian hyperstimulation for IVF with 85% accuracy. CONCLUSION: Follicle-stimulating hormone response to CC predicts subsequent follicular response to controlled ovarian hyperstimulation.

Stimulation with human menopausal gonadotropin versus follicle-stimulating hormone after pituitary suppression in polycystic ovarian syndrome.

Stimulation with human menopausal gonadotropin (hMG) or follicle-stimulating hormone (FSH) was compared in 34 patients with polycystic ovarian syndrome after pituitary gonadotrope suppression with buserelin acetate. No differences were seen in the hormone parameters observed. Also, the duration of the stimulation period and the dose of gonadotropin used were the same. In both groups a multifollicular response was seen. Oocyte retrieval and in vitro fertilization resulted in identical ratios of mature to total oocytes and cleavage rates. Nine pregnancies occurred, four in the hMG group and five in the FSH group. Of the nine pregnancies, two were the result of transfer of frozen-thawed embryos in estradiol and progesterone substituted cycles.

The first attempt at IVF treatment. Results and requirements for a satisfactory success rate.

The purpose of this study was to report the success rate of the first IVF treatment in 161 patients who attended our department in 1988. The indications for IVF were tubal damage in 84 couples (52.1%), unexplained infertility and endometriosis (with patent tubes) in 61 couples (37.9%), and polycystic ovarian syndrome in 16 couples (10%). Clinical pregnancies were diagnosed in 40 patients, giving an overall clinical pregnancy rate of 35.4% per embryo transfer. In the group of patients with unexplained infertility or endometriosis one in three of the embryo transfer cycles will predictably result in a birth, one in four in the group of patients with tubal damage or polycystic ovarian syndrome. These results invite discussion of the possible reasons for the success of our IVF program.

Duration of the latency period in preterm premature rupture of the membranes. Maternal and neonatal consequences of expectant management.

111 pregnancies complicated with premature rupture of the membranes (PROM) at a gestational age between 20 and 34 weeks, were observed prospectively with expectant management. Median duration of the latency period was 7 (0-109) days. The duration of the latency period was inversely related to the gestational age at PROM. Intra-uterine death ensued in 9.9% of the pregnancies. Clinical chorioamnionitis ensued in 12.6% of the pregnancies. Eight (7.6%) neonates developed sepsis. None of the babies died as a consequence of sepsis alone. Of the 43 (41.0%) neonates who developed idiopathic respiratory distress syndrome (IRDS), 8 (7.6%) babies died. The perinatal mortality rate was 18.6%. The study seems to justify the expectant management of PROM pregnancies of less than 34 weeks of gestation.

Benefits of continuous infusion epidural analgesia throughout vaginal delivery.

Two groups of nulliparous women with fetuses in singleton vertex presentation received continuous infusion epidural analgesia (EDA) with bupivacaine: group A (90 parturients) without infusion analgesia in the second stage of labor and group B (90 parturients) with infusion analgesia throughout delivery. The groups were compared regarding pain relief, duration of the second stage, persistent malrotation of the fetal head, and rate of instrumental vaginal delivery. The continuous infusion EDA gave satisfactory pain relief in 93.3% of the parturients in group A and 97.8% in group B. The duration of second stage was the same in both groups. There were more persistent malrotations of the fetal head in group A, but the malrotation did not affect the mode of delivery. The rate of instrumental vaginal delivery was 25.5% in both groups. The main cause of operative intervention was delay in the second stage. When the continuous infusion technique is used, it seems unreasonable to discontinue the EDA and thereby deprive the parturient of analgesia during the second stage.

GnRH-agonist therapy in women with the polycystic ovarian syndrome: effects on ovarian volume and on gonadotropin and sex steroid levels.

Eleven patients with infertility and polycystic ovarian syndrome were treated with the GnRH agonist buserelin, 100 micrograms administered intranasally 6 times daily. The ovarian volume and morphology were monitored by vaginal sonography, and serum levels of hormones were measured by immunoassay. The mean ovarian volume was reduced from 13.0 +/- 4.1 cm3 to 9.1 +/- 3.1 cm3 after 42 days of treatment, p less than 0.001. The number of discernible ovarian microcysts was reduced from 11.9 +/- 2.1 to 9.6 +/- 2.9, p less than 0.05. The gonadotropin levels were reduced in all patients; however, there was no direct relationship between the reduction in ovarian volume loss and the concomitant decrease in LH or FSH levels. The levels of testosterone and androstenedione were normalized, whilst estradiol was suppressed to postmenopausal levels during the treatment period. The decrease in ovarian volume and the suppressed levels of ovarian steroids therefore seem to be related to the inhibition of the pituitary-ovarian axis with the GnRH agonist.

In vivo fertilization procedures in infertile women with patent fallopian tubes: a comparison of gamete intrafallopian transfer, combined intrauterine and intraperitoneal insemination, and controlled ovarian hyperstimulation alone.

This prospective study was undertaken to evaluate the relative efficacy of three in vivo methods of assisted fertilization in 150 infertile women with patent fallopian tubes: gamete intrafallopian transfer (GIFT), combined intrauterine and direct intraperitoneal insemination (IUI+DIPI), and controlled hyperstimulation (COHS) alone. The clinical pregnancy rate was highest in the IUI/DIPI and GIFT groups: IUI/DIPI, 29.3%; GIFT, 28.6%; and COHS, 8.9%. We believe that controlled ovarian hyperstimulation combined with IUI and DIPI is a good alternative to GIFT.

The impact of insulin resistance on the outcome of ovulation induction with low-dose follicle stimulating hormone in women with polycystic ovary syndrome.

In this study we examined the possible correlation between insulin metabolism and outcome of gonadotrophin stimulation in infertile clomiphene citrate resistant women with polycystic ovary syndrome (PCOS). The patient group comprised 42 women who were entered into the study in a consecutive fashion. Following performance of the CIGMA (continuous infusion of glucose with model assessment) test, 17 women were classified as insulin resistant and 25 women as non-insulin resistant. Each woman received up to two cycles of low-dose follicle stimulating hormone (FSH) stimulation starting with 75 IU of FSH for 1 week, giving a total of 70 cycles performed. The insulin resistant PCOS women required more gonadotrophin and a longer time to achieve follicular maturation. By multiple regression gonadotrophin consumption correlated best with CIGMA value but not with fasting insulin concentration or body mass index. In the insulin resistant PCOS women 10 out of 29 cycles were cancelled due to a multifollicular response, while only one of 41 cycles was cancelled in the non-insulin resistant PCOS women. Although ovulation rate in completed cycles was similar between the groups, the conception rate was significantly better in the non-insulin resistant PCOS women. In conclusion, in PCOS women insulin resistance seems to be an unfavourable condition resulting in an elevated cancellation rate and a low conception rate following low-dose FSH stimulation.

Assisted fertilization in infertile women with patent fallopian tubes. A comparison of in-vitro fertilization, gamete intra-fallopian transfer and tubal embryo stage transfer.

A comparison of the relative efficacy of in-vitro fertilization with uterine embryo transfer (IVF), tubal embryo stage transfer (TEST) and gamete intra-Fallopian transfer (GIFT) was performed in infertile patients with patent Fallopian tubes. A total of 150 couples with unexplained infertility, peritoneal endometriosis or reduced semen quality were included in the study. The three groups were comparable with regard to age distribution, indications, semen parameters, stimulation regimens, response to stimulation and numbers of oocytes retrieved. In the IVF and TEST groups there was no cleavage in 24% and a cleavage rate of only 47.6%. The highest cleavage rate was obtained in the endometriosis patients. The pregnancy rate was highest in the two groups in which in-vitro fertilization was performed, IVF = 45.7%, TEST = 37.9%, GIFT = 26.2%. To obtain one live intrauterine fetus, more oocytes had to be transferred in the GIFT group compared to the number of embryos in the IVF group, 14.4 versus 6.2, P less than 0.05. Due to a high success rate of IVF but at the same time a high frequency of no cleavage in cases of unexplained infertility or male subfertility, we recommend IVF as the primary procedure in infertile couples with patent Fallopian tubes.

Ovarian stimulation in previous failures from in-vitro fertilization: distinction of two groups of poor responders.

Forty-three patients who responded poorly to previous stimulation with clomiphene citrate (CC)/human menopausal gonadotrophin (HMG) for IVF were followed during 70 further cycles. Eighteen patients had a normal FSH response to CC in the previous cycle, while 25 had an abnormal FSH response. Three stimulation protocols were used: buserelin/HMG, CC/HMG and HMG only. No difference between the two groups was observed in the dose of HMG used for any stimulation protocol. More cycles were cancelled due to a poor response in the abnormal response group compared to the normal response group. In the completed cycles, the maximum oestradiol level and number of oocytes retrieved were lower in the abnormal response group compared to the normal response group. The total pregnancy rate per patient, including spontaneous conceptions during the study period, was lower in the abnormal response group compared to the normal response group, 4 versus 33%. We conclude that poor responders with an abnormal FSH response to CC have a latent ovarian failure with a low chance of success in further IVF attempts.

[Reduced ovarian function in infertile women. Experiences with the clomiphene test]. / Nedsatt ovarialfunksjon hos infertile kvinner. Erfaringer med klomifentesten.

The authors briefly describe the current understanding of follicular maturation, the influence of FSH on follicular maturation and the regulation of FSH secretion. They discuss the complex mechanisms of the impacts of clomiphene citrate, and how clomiphene citrate can be used in a test of ovarian reserve based on the FSH response. The article reports of the clomiphene citrate challenge test in patients referred to in vitro fertilization.

Heterotopic pregnancy following in vitro fertilization.

We report 4 cases of heterotopic pregnancy following in vitro fertilization. All 4 patients were treated by surgical removal of the ectopic pregnancy products. In 3 patients, the intra-uterine fetus was alive prior to surgery. Two of the 3 gave birth to a healthy baby while the third pregnancy has progressed uneventfully for 12 weeks since the operation.

In-vitro fertilization in infertile women with the polycystic ovarian syndrome.

Forty-four infertile patients with the polycystic ovarian syndrome (PCOS) resistant to other treatment modalities were treated in 58 cycles of IVF after accomplishment of pituitary gonadotroph suppression with a GnRH-agonist. Four cycles were cancelled before oocyte retrieval while embryo transfer was deferred for 10 cycles due to imminent ovarian hyperstimulation syndrome (OHSS). Follicle aspiration yielded 18.8 +/- 9 oocytes per cycle. The cleavage rate was 68%. There was no cleavage in five cycles. The pregnancy rate was 33.3% per embryo transfer. In 32 cycles 9.0 +/- 5 suitable supernumerary embryos were cryopreserved. Transfer of cryopreserved embryos gave three additional pregnancies. The accumulated pregnancy rate per patient was 36%. In clomiphene citrate resistant patients, transfer of cryopreserved embryos was accomplished after secretory transformation of the endometrium by oestradiol/progesterone substitution. Although seven pregnancies ended in a miscarriage, the 'take-home' baby rate was 20%. OHSS ensued in 28 (46.7%) cycles. In PCOS, in-vitro fertilization following pituitary gonadotroph suppression seems a treatment alternative with pregnancy rates comparable to normo-ovulatory women with tubal factor infertility. However, the incidence of OHSS is high and constitutes the major problem of cycle control.

Polycystic ovary syndrome: low-dose follicle stimulating hormone administration is a safe stimulation regimen even in previous hyper-responsive patients.

We studied 23 women with polycystic ovarian syndrome (PCOS), resistant to clomiphene citrate, who had a previous history of multifollicular ovarian development on gonadotrophin stimulation. Each woman had one cycle of gonadotrophin-stimulating hormone agonist/human menopausal gonadotrophin (GnRHa/HMG) stimulation and then one cycle of low-dose follicle stimulating hormone (FSH) stimulation. All GnRHa/HMG cycles were multifollicular. On the low-dose FSH protocol, 10 cycles were unifollicular, while two to three follicles were observed in nine cycles, and four cycles were multifollicular. The ovarian hyperstimulation syndrome ensued in one of the FSH cycles versus 13 of the GnRHa/HMG cycles. Despite decreasing luteinizing hormone (LH) levels and increasing FSH levels, androgen levels increased during stimulation on both protocols. There was one pregnancy in the GnRHa/HMG cycles versus six pregnancies following the FSH cycles. In conclusion, low-dose FSH administration seems a safe stimulation regimen with a satisfactory conception rate even in PCOS women with a previous record of multifollicular ovarian development.