Premature ovarian insufficiency: a toolkit for the primary care physician.

Premature ovarian insufficiency (POI) refers to the loss of ovarian activity before the age of 40 years, which leads to hypoestrogenism and amenorrhea. The diagnosis of POI in a young woman has potentially life-changing physical and emotional consequences for both the patient and her family. Therefore, it is very important that the diagnosis is correct and that it is made in a timely manner. Unfortunately, the diagnosis and therefore the effective treatment of POI are often delayed, which underlines the need for education of the broad medical community on the issue. A panel of menopause experts reviewed and critically appraised the literature, and present: (1) the diagnostic approach to POI, (2) the investigation of the etiology of this condition, (3) the therapeutic strategy regarding both hormone replacement therapy and fertility, and (4) the long-term follow-up and management for ensuring quality of life, as well as urogenital, cardiovascular, bone and mental health. The ultimate goal of this article is to provide a complete toolkit for the primary care physician to have easy access to all the information needed for the optimal management of women with POI, in the context of evidence-based and personalized medicine.HIGHLIGHTSPremature ovarian insufficiency occurs in 1% of the female population of reproductive age, yet the diagnosis is often delayed, with severe physical and emotional consequences for the patient.Primary care physicians should be aware of the possibility of premature ovarian insufficiency in young women presenting with menstrual irregularity.Prompt initiation of hormone replacement therapy ensures quality of life and prevents osteoporosis and cardiovascular disease.Women seeking fertility should be referred to specialists to discuss assisted reproduction options.

Distinct types of uterine adenomyosis based on laparoscopic and histopathologic criteria.

PURPOSE: To analyze laparoscopically treated cases of adenomyosis based on intraoperative and histopathology findings and to correlate different types with patients' presenting symptoms and characteristics, as well as with the surgical approach. MATERIALS AND METHODS: Sixty-eight women who underwent laparoscopic treatment of adenomyosis at a referral center for gynecological laparoscopy. RESULTS: Four distinct types of adenomyosis could be identified: diffuse, sclerotic, nodular, and cystic (54.5%, 13%, 28%, and 4.5% of cases, respectively). Menorrhagia as the main presenting symptom was significantly more frequent in patients with the diffuse type (84%) compared to those with sclerotic (44%) and nodular (37%) types (p = 0.025 andp = 0.001, respectively). All cases of cystic and nodular adenomyosis were treated by laparoscopic excision of the lesion. Eighty-nine percent of patients with sclerotic adenomyosis were treated with wide laparoscopic excision of the abnormal tissue. Eighty-one percent of patients with diffuse adenomyosis were treated with laparoscopic hysterectomy. CONCLUSIONS: Adenomyosis can be classified in four distinct types with differences in the presenting symptoms, as well as in the ideal surgical approach.

Hysteroscopy in the evaluation of habitual abortions.

OBJECTIVES: To evaluate the incidence of structural uterine anomalies (SUAs) in women with habitual abortion (HA) as diagnosed by means of hysteroscopy and to study hysteroscopy's therapeutic potential with regard to that pathology. METHODS: Forty-eight women with more than three consecutive pregnancy losses which occurred prior to the 20th week were included and hysteroscopy was performed on all of them. RESULTS: Twenty-five women (52%) had a normal hysteroscopy. The remaining 23 women (48%) presented SUAs: nine patients (19%) had intrauterine adhesions, four (8%) had submucous myomas, two (4%) had polyps and eight (17%) had congenital structural uterine anomalies (five cases of septate uterus and three of bicornuate uterus). Patients with abnormal hysteroscopy underwent appropriate therapy, when applicable. In the SUA group, 18 patients (78%) achieved a successful pregnancy, and five patients (22%) had another miscarriage. In the normal hysteroscopy group, eight patients (32%) achieved a successful pregnancy without additional treatment, 15 patients (60%) had recurrent miscarriages, and two patients (8%) had persistent secondary infertility. CONCLUSIONS: SUAs were detected in nearly half of the patients with HA. After appropriate treatment when applicable, 78% of patients with SUAs achieved a successful ongoing pregnancy. Hysteroscopy has much to offer in the diagnosis and treatment of SUAs.

Safety and effectiveness of tinzaparin sodium in the management of recurrent pregnancy loss.

PURPOSE: To assess the safety and efficacy of tinzaparin sodium for the management of recurrent pregnancy loss. METHODS: The study included 62 women with a history of recurrent pregnancy loss and at least one factor of thrombophilic disorder. Of these, 31 received 50 IU/kg of tinzaparin sodium daily (Group A), and 33 received 100 mg of aspirin daily (Group B). RESULTS: Group A subjects (receiving tinzaparin sodium) had six new abortions, whereas Group B subjects (receiving aspirin) had 11 (significant difference). Cases of intrauterine growth restriction (none in Group A and 2 in Group B), placental abruption (one in Group A and 4 in Group B), and preeclampsia (one in Group A and 3 in Group B) were comparable between the two groups. Finally coagulation disorders (none in Group A and 6 in Group B) were significantly fewer in Group A. CONCLUSION: A 50 IU/kg daily dose of tinzaparin sodium seems to be effective for the management of recurrent abortion and has high standards of safety.

No effect of tocolytic therapy with atosiban on maternal serum interleukin-6 and tumor necrosis factor-alpha in threatened preterm labor.

OBJECTIVES: We aimed to evaluate the effect of intravenous administration of tocolytic therapy with an oxytocin antagonist drug (atosiban) on maternal serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels in women with threatened preterm labor. METHODS: The study population consisted of 46 women with a singleton pregnancy admitted to our department with a diagnosis of threatened preterm labor at between 26 and 34 weeks of gestation. Atosiban was administered to all women. Nine women (group A) progressed to delivery within 48 hours of admission. The remaining 37 women were divided in two groups: group B consisted of 16 women who remained undelivered at 48 hours but experienced delivery within 7 days and group C consisted of 21 women who did not deliver within the next 7 days. Maternal serum IL-6 and TNF-alpha levels were assessed in duplicate by a high sensitivity ELISA kit on patient admission and again at the end of treatment with atosiban (36 hours post-admission). RESULTS: Serum IL-6 and TNF-alpha concentrations on admission were significantly higher in group A compared to those found in group B (p = 0.01) and group C (p = 0.04). Comparisons of serum IL-6 values on admission and at 36 hours after the initiation of atosiban treatment were comparable in group A (p = 0.95), group B (p = 0.39), and group C (p = 0.79). Similarly serum TNF-alpha levels on admission were not significantly different compared to those at the end of treatment in all groups (p = 0.85 for group A, p = 0.45 for group B, and p = 0.21 for group C). CONCLUSIONS: No effect of tocolytic therapy with atosiban was observed on serum IL-6 and TNF-alpha levels in women with threatened preterm labor.

Blastocyst biopsy versus cleavage stage biopsy and blastocyst transfer for preimplantation genetic diagnosis of beta-thalassaemia: a pilot study.

BACKGROUND: Trophectoderm biopsy at the blastocyst stage is an emerging approach in preimplantation genetic diagnosis (PGD). This study aimed to compare genotyping success and implantation rates in PGD cycles for beta-thalassaemia following biopsy at the cleavage versus the blastocyst stage, with transfer of blastocysts. METHODS: This pilot study included 20 cycles: Group A: 10 cycles, day 3 blastomere biopsy, day 5 transfer; Group B: 10 cycles, day 5 trophectoderm biopsy, day 6 transfer. Standard-assisted reproduction and laser biopsy procedures were used. Biopsied cells were genotyped using real-time PCR multiplexed with fluorescent microsatellite analysis. RESULTS: In Group A, 131 fertilized eggs developed to 101 embryos suitable for single blastomere biopsy; 76/101 blastomeres were diagnosed (75.2%), 30 unaffected blastocysts were transferred resulting in six pregnancies (eight fetal hearts, 26.7% implantation rate). In Group B, 128 fertilized eggs developed to 53 blastocysts for trophectoderm biopsy (four to five cells), with 50/53 blastocysts diagnosed (94.3%), 21 unaffected blastocysts transferred and 6 pregnancies initiated (10 fetal hearts, 47.6% implantation rate). Overall, nine pregnancies reached >10 weeks gestation and were confirmed unaffected by prenatal diagnosis, with 12 healthy babies born. CONCLUSIONS: This pilot study suggests that trophectoderm biopsy and blastocyst transfer may be more advantageous than cleavage stage biopsy with respect to outcome of PGD for monogenic diseases.

Maternal age and the duration of the second stage of labor.

The purpose of this study was to investigate the relationship between parity, maternal age at delivery, gestational age, and duration of the second stage of labor. In this article a retrospective analysis of deliveries during the period from 2000 to 2005 in our Institution was made. We recorded 208 pregnant women under the age of 20 years, 6,115 between 20 and 40 years, and 188 over the age of 40 years considering parity, duration of second stage of labor, birth weight, and gestation age. The correlation of the above parameters was statistically analyzed. In primigravidas, under the age of 20 years, the second stage of labor was significantly shorter compared to women aged over 40 years, and significantly shorter compared to women between the age of 20 and 40 years. Gestational age at delivery was significantly shorter in women aged over 40 years compared to those under the age of 20 years as well as to those between 20 and 40 years of age. Age was positively correlated to the duration of the second stage of labor and negatively correlated to the gestation age at delivery. In multigravidas, age was negatively correlated to the gestational age at delivery. In primigravidas, maternal age was positively correlated with the duration of the second stage of labor. On the contrary, gestational age at delivery was negatively correlated with maternal age. In multigravidas, a negative correlation between maternal age and gestational age at delivery was statistically significant.

No association between insulin resistance and preeclampsia.

OBJECTIVE: To investigate the possible link between insulin resistance and preeclampsia. METHODS: The study included 30 primigravidas between 28 and 34 weeks of gestation. The study subjects were divided into two groups: Group A consisted of 15 normotensive women of a mean gestational age of 31.6 weeks and group B consisted of 15 preeclamptic women of a mean gestational age of 29.9 weeks. Glucose and insulin levels were measured at 0, 1 and 2 h of an OGTT (after 75 g oral glucose administration). Insulin resistance and sensitivity were evaluated with the use of IR HOMA, QUICKI and IS OGTT. RESULTS: Glucose and insulin levels at 0, 1 and 2 h of the OGTT as well as IR HOMA, QUICKI and IS OGTT were comparable between preeclamptic and normotensive pregnant women. CONCLUSIONS: Our results indicate that preeclampsia is not associated with hyperinsulinaemia and/or insulin resistance, in either the fasting or the postprandial state.

HLA-G in murine peripheral blood after interruption of pregnancy.

HLA-G antigens are highly expressed in maternal peripheral blood during early pregnancy in transgenic mice. In this study, we determined the levels of HLA-G in white blood cells during early pregnancy and after interruption of pregnancy in triple transgenic mice (H-2K(b)/HLA-G, hbeta2m, and hCD2/hCD8-TRI). The pregnancies were interrupted on day 7 using the anti-progesterone agent mifepristone (RU486). Blood samples of 20 pregnant TRI mice were taken and the HLA-G levels were determined on days 2, 4 and 6 of pregnancy and on days 9, 11 and 13 after fertilization. The monoclonal antibody W6/32, specific for monomorphic determinant HLA class I molecules, was used in combination with an immunolocalization method using a photonic microscope. The HLA-G levels increased gradually on days 2, 4 and 6 of pregnancy, and the interruption of pregnancy on day 7 was followed by a decrease of HLA-G levels. The data indicate that pregnancy is characterized by the early presence of HLA-G in maternal peripheral blood in TRI transgenic mice and suggest that HLA-G may serve as a useful indicator for pregnancy maintenance and well-being.

Prediction of preterm delivery by sonographic estimation of cervical length.

BACKGROUND: Identification of pregnant women presenting with threatened preterm labor who are destined to deliver prematurely would greatly assist planning their management. OBJECTIVES: The purpose of the study was to evaluate the ultrasonographic measurement of cervical length as a prognostic factor for predicting preterm birth in cases of threatened preterm labor. METHODS: The study included 104 women with singleton pregnancies who presented with threatened preterm labor at 24-36 weeks of gestation. Cervical length at presentation was evaluated by transvaginal ultrasonography. Other potential prognostic factors, such as previous history of preterm labor, smoking, parity and administration of tocolytics were assessed. All women were observed for preterm delivery within 7 days of presentation. RESULTS: The only significant predictor of preterm delivery was cervical length assessed by ultrasound (p<0.000001, odds ratio 93.3, 95% Cl 10.4-837.1). CONCLUSIONS: Cervical length assessed by transvaginal ultrasonography in women presenting with threatened preterm labor is a powerful predictive tool for progression to preterm delivery.

Infections of the lower female genital tract during childhood and adolescence.

PURPOSE: To review the pathogenesis, clinical presentation, diagnosis and treatment of lower female genital tract infections at a young age. METHODS: Review study. CONCLUSIONS: Lower female genital tract infections at a young age may involve the vulva, the vagina and, less frequently, the fallopian tubes. Good knowledge of the physiology and anatomy of the respective areas plays an important role in the diagnosis and treatment of vulvovaginitis. Candida albicans is the most frequent cause of infection, while Gardnerella vaginalis, Chlamydia trachomatis, Mycoplasma, and Trichomonas vaginalis are rarer ones. The clinical presentation includes a variety of symptoms and signs, with vaginal discharge being the prominent one. Treatment should be causative after careful investigation while preventive advice is mandatory.

Blastocyst versus early cleavage embryo transfer: a retrospective analysis of 4,165 transfers.

PURPOSE: To compare the clinical outcomes after the transfer of blastocysts versus early cleavage embryos in assisted reproduction technologies (ART). METHODS: A retrospective analysis of all the ovarian stimulation-in vitro fertilization-embryo transfer cycles performed at the Centre for Human Reproduction, Athens, Greece, between June 1997 and December 2001. RESULTS: The number of blastocysts transferred per ET was significantly lower compared to that of all early cleavage embryos. The implantation rate of blastocysts was significantly higher compared to that of all other modes of transfer. Clinical pregnancy rate after the transfer of blastocysts was significantly increased compared to that after transfer of any early cleavage embryo. The viable pregnancy rate after the transfer of blastocysts was significantly increased only compared to that after the transfer of day-2 embryos. There were no significant differences regarding the multiple gestation rates among the various modes of transfer. CONCLUSION: The use of blastocysts in ART is beneficial when compared to that of day-2 embryos and at least comparable to that of day-3 embryos. Blastocyst culture and transfer remains a favourable and promising option in ART.

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in plasma/serum and urine of women during term and threatened preterm labor: a clinical approach.

OBJECTIVE: To explore the concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in plasma, serum and urine of women during term and threatened preterm labor. METHODS: Plasma and urine proMMP-9 as well as serum and urine TIMP-1 were evaluated in 60 healthy pregnant women; 20 of them presented in term labor following an uncomplicated pregnancy, 20 of them presented with threatened preterm labor and intact membranes at 24-36 gestational weeks and 20 of them were at 24-40 gestational weeks with no evidence of uterine contractions or other pregnancy complications. Data were analyzed with non-parametric statistical tests and cut-off values were determined with receiver operator characteristic curves. RESULTS: ProMMP-9 values were significantly higher and TIMP-1 values were significantly lower in cases with uterine term or preterm contractions compared to non-labor status; and in cases with preterm contractions that progressed to true preterm labor compared to those in which contractions were arrested. CONCLUSIONS: Alterations in the concentrations of proMMP-9 and TIMP-1 can be detected in plasma or serum and urine of pregnant women experiencing term or preterm uterine contractions. The altered values of proMMP-9 and TIMP-1 could possibly identify the inevitable progress of preterm contractions to true preterm labor.

Triplet pregnancy after oocyte donation in women 46 years of age and older: three case reports.

PURPOSE: Presentation of three triplet pregnancies achieved in women 46 years of age and older with the use of donated oocytes. MATERIAL & METHODS: Two healthy perimenopausal women 46 and 48 years old and one healthy menopausal woman 48 years old, requesting fertility options. All of them followed oocyte donation programs resulting in triplet pregnancy. Maternal as well as perinatal complications, mode of delivery and birth weight are reported. RESULTS: Three triplet pregnancies were achieved using donated oocytes. Prenatal diagnosis was reassuring. Preterm rupture of membranes, preterm labor and gestational diabetes complicated the pregnancies. Cesarean section was the mode of delivery for all the cases giving birth to nine healthy neonates weighing between 1,130 and 2,450 g. No postpartum complications were encountered. CONCLUSIONS: Triplet pregnancies achieved with the use of donated oocytes at a very advanced maternal age represent high-risk obstetrical cases. Cautious prenatal evaluation of maternal health and intensive antenatal surveillance are imperative principles allowing the most favorable outcome of these pregnancies.

Alterations in Thl/Th2 cytokine concentrations in early neonatal life.

OBJECTIVE: To determine postnatal changes in neonatal serum concentrations of interferon-gamma (IFN-gamma), interleukin-4 (IL-4) and its soluble receptor (sIL-4R). METHODS: Forty-five healthy term neonates, 25 of the neonates' mothers and 27 healthy adults (controls) participated in the study. Cytokine concentrations were measured in blood samples from the umbilical cord, from the neonates on the 1st and 5th day after birth, from mothers and from controls. RESULTS: IFN-gamma concentrations were significantly lower in the umbilical cord, compared to concentrations in the controls (p < 0.04), and increased significantly from the umbilical cord to levels in neonates on day 5 (p < 0.03). In mothers and the umbilical cord, IFN-gamma concentrations were dependent on the mode of delivery, being higher after vaginal delivery than after elective Cesarean section (p < 0.005; p < 0.006, respectively). IL-4 concentrations in the umbilical cord for 1-day and 5-day neonates were significantly elevated compared to those in mothers (p < 0.001; p < 0.0007; p < 0.0001, respectively) and controls (p < 0.05; p < 0.01; p < 0.006, respectively). sIL-4R concentrations in all neonatal samples were significantly elevated compared to those in controls (p < 0.0001), the highest being found in 1-day-old neonates. A strong negative correlation was found between IL-4 and sIL-4R concentrations in 1- and 5-day-old neonates (r = -0.48, p < 0.002; r = -0.45, p < 0.0065, respectively). Moreover, IFN-gamma/IL-4 ratio increased significantly from the umbilical cord to 5 days of life (p < 0.03). CONCLUSIONS: Our findings indicate an earlier development of IL-4 than IFN-gamma, which could be viewed as a developmental characteristic in the ontogeny of the immune system.

Abnormal fetal heart rate patterns during the active phase of labor: the value of fetal oxygen saturation.

OBJECTIVE: To determine the predictive value of intrapartum fetal oxygen saturation (SO2) for prediction of an umbilical artery pH less than 7.15 at birth in labors complicated by abnormal fetal heart rate traces. STUDY DESIGN: Eighty-five primigravidas in spontaneous labor complicated by abnormal fetal heart rate traces underwent fetal SO2 monitoring using the fetal pulse oximetry technique. Cases with an SO2 of < 30% were delivered by Cesarean section. Umbilical artery pH was measured at birth in all women. RESULTS: With the value set of 30% as the cut-off point of fetal oxygen saturation, the positive predictive value for umbilical artery pH of < 7.15 was 61.5% and the negative predictive value was 95.8%, with a sensitivity of 72% and a specificity of 93%. CONCLUSIONS: Fetal pulse oximetry is a promising technique for assessment of fetal well-being during labor and may decrease the number of unnecessary Cesarean sections.

Creation of a neovagina following Williams vaginoplasty and the Creatsas modification in 111 patients with Mayer-Rokitansky-Küster-Hauser syndrome.

OBJECTIVE: Evaluation of the Creatsas modification of Williams vaginoplasty for the creation of neovagina in patients with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome). DESIGN: Record of perioperative and postoperative results and complications. Follow-up evaluations of patients yearly after the operation. SETTING: Division of Pediatric-Adolescent Gynecology and Gynecologic Corrective Surgery, University of Athens (tertiary referral center). PATIENT(S): One hundred eleven patients with MRKH syndrome. INTERVENTION(S): Surgical creation of neovagina using the Williams vaginoplasty technique (group A: 10 patients) or the Creatsas modification of the previous method (group B: 101 patients). MAIN OUTCOME MEASURE(S): Length and width of the neovagina, and the quality of sexual life postoperatively. RESULT(S): A functioning vagina of 10 to 12 cm depth and 5 cm width was created in eight of the patients in group A (80%) and in 98 of those in group B (97.02%). A vagina of 7 to 9 cm depth and 2 to 3 cm width was created in the rest of the patients in both groups. In group A, two wound openings were reported (20%); in two of the patients hemorrhage occurred during the first intercourse, compared to none in group B. A satisfactory sexual life was reported from 94.4% of the patients and an adequate one from 4.16% of them. CONCLUSION(S): The Creatsas modification of Williams vaginoplasty is a simple and effective technique for the creation of a functioning neovagina in young women with vaginal aplasia.

Long term effects of Tibolone on postmenopausal women with uterine myomas.

OBJECTIVES: The aim of the present study is to evaluate the long term effects of Tibolone (Livial) on uterine myomas volume as well as on uterine arteries pulsatility index (PI) in postmenopausal women. METHODS: This study included 66 naturally menopausal women. Twenty of them (group A) had no uterine myomas; 23 of them (group B) had a single, asymptomatic, intramural or subserous myoma of a maximum diameter less or equal than 2 cm; 23 of them (group C) had a single, asymptomatic, intramural or subserous myoma of a maximum diameter between 2 and 5 cm. The volume of the myomas as well as the pulsatility index of the uterine arteries was assessed by transvaginal ultrasonography every 6 months after administration of Tibolone (2.5 mg daily). RESULTS: No statistically significant difference on myomas volume was found after a 3-year period of Tibolone administration. The uterine artery basal PI was significantly higher in group A compared to that of groups B and C. After 6 months of Tibolone administration the PI in group A was significantly lower compared to the basal one whereas in groups B and C was significantly higher compared to the basal value. CONCLUSIONS: Our results suggest that treating postmenopausal woman with Tibolone on a long-term basis: (a) does not increase the volume of uterine myomas and (b) has an early effect on uterine haemodynamics (decrease of PI in women without myomas and increase of PI in women with myomas).