A. La Marca

Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach

BACKGROUND Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. METHODS An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. RESULTS We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value <0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. CONCLUSIONS This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response.

Bone mineral density and biochemical markers of bone turnover in peri- and postmenopausal women.

Abstract. Bone mineral density (BMD) measured by densitometry is the elective parameter for the diagnosis of osteopenia and osteoporosis. Biochemical markers have been proposed as sensitive indicators of high bone turnover and for monitoring response to antiresorptive treatment. We conducted a retrospective study to investigate the values of biochemical markers of bone metabolism with a view to early diagnosis of osteoporosis and monitoring of hormone replacement and calcitonin therapy. The subjects were 415 women, mean age 51 ± 8 years (43–62 years) in peri- and postmenopause, recruited at the Menopause Center of Obstetrics and Gynecology Department of Siena University and divided in five groups. Bone densitometry was performed in all subjects and blood samples were taken for assayed biochemical markers, that is, [osteocalcin (OC), parathyroid hormone (PTH), type 1 procollagen (PICP), and calcitonin (CT)].Three groups of women were divided into two subgroups: those with normal and those with low BMD (<1 SD). Basal concentrations of PCP1, OC, PTH, and CT were compared in the various groups. Two groups of postmenopausal women with BMD below the normal were treated with estrogen replacement therapy and unmodified eel calcitonin.We evaluated whether some of these biochemical markers of bone turnover could help identify women with low BMD and whether they could be useful for monitoring the results of antiresorptive therapies.Markers of bone formation (PICP and OC) make it possible to distinguish women with high turnover who are at risk for osteoporosis from women with low turnover in menopause. A good correlation was also found between changes in levels of these markers and changes in BMD during treatments, which suggests that the PICP and OC would be useful for monitoring response to antiresorptive therapy.

Hormonal and clinical effects of GnRH agonist alone, or in combination with a combined oral contraceptive or flutamide in women with severe hirsutism

The objective of this prospective randomized study was to evaluate and compare the hormonal and clinical effects of long-acting gonadotropin-releasing hormone (GnRH) agonist and a combination of GnRH agonist with combined oral contraceptive (COC) or flutamide in women with polycystic ovary syndrome (PCOS). Thirty-five hirsute women with PCOS, ranging in age from 19–27 years, were randomly divided into three groups: group A treated with GnRH agonist (n = 12), group B (n = 12) treated with GnRH agonist plus COC and group C (n = 11) treated with GnRH agonist plus flutamide for 6 months. Before, at the end and 6 months after the end of treatment, blood samples were drawn from all women (in early follicular phase in those with menstrual cycles) to measure ovarian and adrenal androgens, gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), estradiol and estrone plasma levels. The results showed that all three protocols had good therapeutic efficacy. A significant reduction in hirsutism was observed in all patients after 6 months of therapy, the Ferriman–Gallwey scores dropping to 9 ± 3 in group A, 10 ± 4 in group B and 11 ± 5 in group C. Six months after the end of therapy, the hirsutism score continued to be significantly reduced in all groups. After 6 months of therapy, a reduction in plasma levels of LH, FSH, estrone, estradiol, testosterone, free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS) was observed in all groups although this was more pronounced in group B and group C. These therapies may be the basis of future treatments that quickly reduce hirsutism and remove its causes by reducing the secretion of ovarian and adrenal androgens and by blocking androgen receptors.

Short-Term Treatment of Uterine Fibromyomas with Danazol

The aim of this study was to evaluate the effects of danazol in reducing the volume of fibromyomas and in the treatment of associated symptoms. Twenty women (34–42 years) with uterine fibromyomas were treated with 400 mg/day of danazol for 4-month periods. The women underwent ultrasound examination to determine their uterine volume at enrollment in the follicular phase and after 2 and 4 months. The examination was repeated by the same sonographer 3 and 6 months after the end of therapy. Blood samples were taken on the same days for LH, FSH, estradiol and progesterone assays. After therapy, fibromyoma volume decreased significantly (p < 0.01) by an average of 23.6 ± 5%. All patients experienced partial or complete relief of symptoms while using danazol. Three and six months after the end of treatment the fibromyoma volume had only increased slightly with respect to the volume at the end of therapy, but was still lower than the starting volume. The present study shows the efficacy of danazol at a dose of 400 mg/day for 4 months in reducing the volume of fibromyomas and associated symptoms. The mechanism by which danazol reduces the volume of fibromyomas may be due to reduced estrogen concentrations and to its antiprogesterone effects on uterine myomas.

Evaluation of Treatment of Hyperemesis gravidarum Using Parenteral Fluid with or without Diazepam

Objective: Hyperemesis gravidarum is a relatively unknown disease, and is generally self-limiting. In some women the symptoms are so severe as to threaten the health of the mother and fetus. Therapies proposed for hyperemesis gravidarum are therefore rather empirical. Medical treatment includes parenteral fluid replacement and nutrition, electrolytes, antiemetics, vitamins, sedation and psychological counseling. Diazepam and benzodiazepins have been widely studied in pregnancy but the results are contradictory. The aim of the present study was to investigate the efficacy of parenteral fluids with vitamins, with or without diazepam sedation. Methods: Fifty women with hyperemesis gravidarum were enrolled in the study. They were treated with infusions of normal saline, glucose, vitamins and randomly with diazepam. Results: The results show that the mean stay in the hospital was shorter in the diazepam group: 4.5 ± 1.9 vs. 6 ± 1.6 days (p < 0.05) and readmission to the hospital was 4% in the diazepam group versus 27% in other group (p < 0.05). There was a significant reduction in nausea in the diazepam group (p < 0.05). A significant reduction in vomiting was observed in both groups. No side effects or congenital neonatal malformations were found in the diazepam group. Conclusions: Intravenous administration of fluids and vitamins is the standard treatment for women hospitalized for hyperemesis gravidarum. The addition of diazepam to the treatment is effective in reducing nausea and does not have teratogenic effects.

Effects of flutamide on pituitary and adrenal responsiveness to corticotrophin releasing factor (CRF).

Flutamide is a non‐steroid antiandrogen that specifically blocks the androgen receptor. We have investigated the effect of flutamide treatment on the adrenal androgen response to corticotrophin releasing factor (CRF) in eight patients with polycystic ovary syndrome (PCOS).

Human chorionic gonadotropin, thyroid function, and immunological indices in threatened abortion

Objective To evaluate the role of thyroid hormones in maintaining early pregnancy and to examine the association between thyroid physiological functions and immunological parameters. Methods Forty-five pregnant women with a clinical diagnosis of threatened abortion and a live fetus and 30 normal pregnant women were included in the study. Blood samples were taken on admission to the hospital. The patients were divided retrospectively into two groups on the basis of outcome: 1) 31 women who did not miscarry (positive outcome) and 2) 14 women who miscarried (negative outcome). Plasma TSH, free triiodothyronine (fT3), free thyroxine (fT4), hCG, immunoglobulin (Ig) G and IgM concentrations and blood counts were determined in each patient. Results Human chorionic gonadotropin was significantly higher in women who did not abort (39.4 ± 16.9 IU/mL) than in women who miscarried (17.6 ± 14.8 IU/mL, P < .001). Free thyroxine but not fT3 was lower in patients with negative outcome (1.25 ± 0.26 ng/mL compared with 1.98 ± 0.22 ng/mL, P < .001) and IgG and IgM plasma levels were higher (780 ± 500 ng/mL compared with 470 ± 300 ng/mL and 930 ± 400 ng/mL compared with 650 ± 280 ng/mL, respectively, P < .05). Plasma TSH levels were higher in patients with negative outcomes (1.72 ± 0.84 mIU/mL compared to 1.01 ± 0.41 mIU/mL, P < .001). Plasma concentrations of hCG and thyroid hormones were significantly correlated with peripheral blood lymphocyte and neutrophil counts only in the group of women who aborted. Conclusion Our results indicate that maternal immune response, trophoblast function, and maternal thyroid function are somehow correlated. The presence of low concentrations of hCG and fT4 and high levels of TSH and gamma globulins in women with threatened abortion suggests a negative outcome for the pregnancy.

Combination of statins and hormone replacement therapy in postmenopausal women is associated with increased bone mineral density.

Recent studies have shown that statins might be potent inhibitors of bone resorption and osteoclast number ,and there is evidence for their bone anabolic effects. Statin treatment seems to protect against non-pathological fractures in older women. However ,contradictory findings have been obtained. In this retrospective study we found that postmenopausal women on statins and hormone replacement therapy (HRT) showed higher bone mineral density than women on HRT alone. This evidence provides further confirmation of the effect of statins on bone turnover and shows that the combination of HRT and statins reduces the risk of bone fracture by virtue of the antiresorptive effect of HRT and the anabolic and antiresorptive effects of statins.

Comparison of biochemical markers of bone turnover and bone mineral density in different groups of climacteric women

In the present study we evaluated plasma levels of two markers of bone turnover (osteocalcin (OC) and urinary pyridinium cross-links) in association with bone mineral density (BMI) in different groups of climacteric women. We have investigated 158 women in pre- ,peri- and postmenopause. Blood and urine samples for assay of hormones and markers were collected and bone mineral density (BMD) was measured by DEXA densitometry in the distal tenth of the non-dominant forearm. There was a significant increase in mean absolute levels of both markers in perimenopause and women in natural and surgical menopause, with respect to women in premenopause. There was a significant correlation between OC and deoxypyridoline (DPYR) in peri- and postmenopause groups. In peri- and postmenopause groups ,BMD was correlated with an increase in the biochemical markers of bone remodeling. In the present study ,OC and DPYR were found to have good sensitivity for identifying perimenopausal women with pathological BMD. The present results reveal a positive and significant correlation between DPYR and OC ,inversely proportional to BMD ,during hormone replacement therapy. These markers therefore turn out to be sensitive not only for monitoring severe pathology of bone turnover ,but also for monitoring slight physiological deficits in bone equilibrium beginning in perimenopause.

Thyroid function in early pregnancy I: Thyroid-stimulating hormone response to thyrotropin-releasing hormone

Maternal thyroid function in pregnancy is influenced by many factors. This study was undertaken to clarify the mechanism of thyroid regulation in the first trimester of normal pregnancy. We performed the thyrotropin-releasing hormone (TRH) test in eight women in the first trimester (week 6-9) of pregnancy and ten normal women in early follicular phase. Basal plasma levels of free triiodothyronine and free thyroxine were within the normal range in both groups, whereas thyroid-stimulating hormone (TSH) was at the lower limit of the normal range in pregnant women. TRH stimulation evoked a TSH response with a peak of 14.1 +/- 1.2 mIU/ml at 30 min. In control subjects TSH increased in response to TRH with a peak of 7.4 +/- 1.1 mIU/ml at 30 min. Statistical analysis with Students t test revealed significantly higher TSH levels (p < 0.01) in pregnant women. The most striking finding was the enhanced responsiveness of TSH to TRH stimulation while the thyroid hormones, free triiodothyronine (fT3) and free thyroxine (fT4), remained in the normal range. This response was similar to that observed in central hypothyroidism. These results suggest that the reduction in maternal pituitary TSH levels is due to human chorionic gonadotropin (hCG) inhibition of TRH secretion.