Juan A. Vanrell

Increased risk of pre-eclampsia and fetal death in Hiv-infected pregnant women receiving highly active antiretroviral therapy

Background:Pre-eclampsia and/or fetal death have increased sharply in HIV-infected pregnant women receiving HAART. Methods:The occurrence of pre-eclampsia or fetal death was analysed in women who delivered after at least 22 weeks of gestation for all women (January 2001 until July 2003) and for HIV-infected women (November 1985 until July 2003). Results:In 2001, 2002 and 2003, the rates per 1000 deliveries of pre-eclampsia and fetal death, respectively, remained stable in all pregnant women at 25.4, 31.9 and 27.7 (P = 0.48) and 4.8, 5.8, and 5.0 (P = 0.89) (n = 8768). In 1985–2000 (n = 390) to 2001–2003 (n = 82), rates per 1000 deliveries in HIV-infected women rose from 0.0 to 109.8 (P < 0.001) for pre-eclampsia and from 7.7 to 61.0 (P < 0.001) for fetal death. In all pregnant women, factors associated with pre-eclampsia or fetal death were multiple gestation [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI), 2.3–5.6; P < 0.001], HIV infection (adjusted OR, 4.9; 95% CI, 2.4–10.1; P < 0.001), multiparity (adjusted OR, 0.76; 95% CI, 0.58–0.98; P = 0.040) and tobacco smoking (adjusted OR, 0.65; 95% CI, 0.46–0.90; P = 0.010). The use of HAART prior to pregnancy (adjusted OR, 5.6; 95% CI, 1.7–18.1; P = 0.004) and tobacco smoking (adjusted OR, 0.183; 95% CI, 0.054–0.627; P = 0.007) were risk factors in HIV-infected women. Conclusions:HIV infection treated with HAART prior to pregnancy was associated with a significantly higher risk for pre-eclampsia and fetal death.

Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women.

BACKGROUND The main goals of estrogen replacement therapy (ERT) are the prevention of osteoporosis and cardioprotection and the improvement of quality of life (QL). Androgens and tibolone therapy may increase bone mineral density (BMD) to a greater extent than ERT and offer an increase in QL. Lipid and cardiovascular effects, however, are still a major concern. AIM To evaluate whether the addition of a weak androgen to ERT may improve postmenopausal bone loss and sexual activity without adverse effects on lipid pattern and to compare these effects with those observed after tibolone therapy. SUBJECTS AND METHODS This prospective study enrolled 120 surgical postmenopausal women; of these, 96 completed the 1-year follow-up. Patients were allocated to one of four groups. The first group (A; n = 23) received 4 mg of estradiol valerate plus 200 mg of enanthate of dihydroandrosterone im monthly. The second group (E; n = 26) received 50 microg/day of transdermal 17-b-estradiol continuously; the third (T; n = 23) received 2.5 mg of tibolone every day; and finally, the fourth group (C; n = 24) constituted a treatment-free control group. Bone mass (dual X-ray absorptiometry), serum total cholesterol, HDL, LDL, triglycerides, apolipoproteins A1 and B and sexual activity were evaluated before starting therapy and at the end of follow-up. RESULTS All active treatment groups showed an increase in BMD. This increase was higher in the A treatment group (4.08% P < 0.01). Sexuality improved significantly with therapy; however, tibolone and androgens increased scores to a greater extent than ERT. Androgen therapy was associated with significant increases in total cholesterol, LDL and triglycerides. Cholesterol and LDL fall into groups E and T, HDL into groups A and T and triglycerides in group T only. CONCLUSION The combined regimen of androgens and ERT increased vertebral bone mass and enhance sexual activity in postmenopausal women equal to that of tibolone and to a greater extent than ERT alone; its effects on lipids, however, are clearly adverse.

Relationship between skin collagen and bone changes during aging.

There is evidence that skin collagen content and bone mass are influenced by estrogen deficiency, both of them declining in the years following menopause. The aim of our study was to analyze the relationship between changes in skin collagen content and bone mass during aging. A total of 76 nulliparous women who had been admitted for surgery of non-malignant processes were studied. All subjects were arranged into five age-groups (from 20 to 60 years). Bone mineral density was measured by dual photon absorptiometry and expressed in g/cm2 as the mean of the second to fourth lumbar vertebrae. Additionally, in all patients skin biopsies were taken from a non-sun exposed site in the lower abdomen (4 cm above the pubic symphysis) and osteocalcin levels were determined. Collagen decreased significantly with age after the 40s (P < 0.001) and after menopause (P < 0.001). Changes in bone mass were closely related to those detected in collagen (r = 0.586; P < 0.0001). In conclusion, our data suggest that bone mass and skin collagen decline in parallel with aging and that the hypoestrogenism developing in postmenopausal years has a significant effect on skin collagen content. Nevertheless, the question of whether osteoporosis is an intrinsic collagen disorder remains to be demonstrated.

Mesonephric adenocarcinoma of the uterine corpus: CD10 expression as evidence of mesonephric differentiation.

Mesonephric (wolffian) neoplasms of the female genital tract are infrequent and found in sites where embryonic remnants of wolffian origin are usually detected, such as the uterine cervix, broad ligament, mesosalpinx, and ovary. Their diagnosis is difficult because of the absence of specific immunohistochemical markers for mesonephric derivatives. We present the first report of adenocarcinoma of mesonephric type arising as a purely myometrial mass without endometrial or cervical involvement in the uterine corpus of a 33-year-old woman. The tumor showed a combination of patterns, with retiform areas, ductal foci, and small tubules with eosinophilic secretion, which merged with solid sheets of cells with a sarcomatoid appearance. Immunohistochemically, neoplastic cells were diffusely positive for cytokeratin 7, epithelial membrane antigen, and CD15 and focally positive for BerEP4 and vimentin. A hitherto unreported feature was the positivity for CD10 in neoplastic cells, which was also present in a large number of control tissues obtained from male mesonephric derivatives and female mesonephric remnants and tumors. Furthermore, CD10 was negative in controls from müllerian epithelia of the female genital tract and in their corresponding tumors. Therefore, the expression of CD10 by mesonephric remnants may be useful in establishing the diagnosis of tumors with mesonephric differentiation.

Severe ovarian hyperstimulation syndrome: role of peripheral vasodilation

Objective To investigate the pathogenesis of the systemic hemodynamic disturbance and the renal production of vasodilator prostaglandins (PGs) in the ovarian hyperstimulation syndrome. Design Prospective longitudinal study. Setting Assisted Reproduction Unit of the Hospital Clinic i Provincial in Barcelona. Patients Five in vitro fertilization patients with ascites because of severe ovarian hyperstimulation syndrome. Main Outcome Measures Measurement during the syndrome and 4 weeks after recovery of the following: cardiac output, arterial pressure, estimated peripheral vascular resistances, hematocrit, standard renal function tests, plasma renin activity, plasma aldosterone, norepinephrine and antidiuretic hormone concentrations, and urinary excretion of PGE 2 and 6-keto-PGF 1α . Results During the syndrome, all patients showed arterial hypotension (74.2±3.8 versus 85.8±1.0mm Hg), tachycardia, increased cardiac output (6.4±0.2 versus 4.4±0.1L/min), low peripheral vascular resistance (929±52 versus 1,568±51dyn/sec per cm −5 ), high plasma levels of renin (72±25 versus 0.5±0.1ng/mL per h −1 ), norepinephrine (639±141 versus 203±21pg/mL) and antidiuretic hormone (6.1±1.6 versus 1.5±0.1pg/mL), and increased urinary excretion of PGE 2 (551±152 versus 106±44pg/min) and 6-keto-PGF 1α (470±76 versus 99±11pg/min). No evidence of hemoconcentration, as assessed by hematocrit, was observed in any patient. Conclusions (1) Severe ovarian hyperstimulation syndrome is related to marked arteriolar vasodilation that leads to underfilling of the arterial vascular compartment and stimulation of endogenous vasoconstrictor systems and (2) the increased urinary excretion of PGs probably represents a homeostatic response to antagonize the renal effects of these systems.

Inhibin, follicle-stimulating hormone, and age as predictors of ovarian response in in vitro fertilization cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment.

OBJECTIVE Our purpose was to determine the relative power of basal inhibin and follicle-stimulating hormone (defined before treatment) and the womans age both as single and combined predictors of ovarian response in an in vitro fertilization program where pituitary desensitization was routinely used. STUDY DESIGN The study was a retrospective analytic investigation of 120 women undergoing the first cycle of in vitro fertilization. Forty consecutive cycles canceled because of poor follicular response were initially selected. As a control group, the nearest completed in vitro fertilization cycles before and after each canceled cycle (i.e., the closest cycles in temporal relationship to the index cycle) were used. RESULTS The mean age and basal follicle-stimulating hormone level were significantly higher in the canceled than in the control group, whereas the basal inhibin level was significantly higher in the latter. Follicle-stimulating hormone and inhibin alone, with an accuracy (predictive value of ovarian response) of 70%, were better predictors of cancellation than age was. Any two or all three of these variables studied did not improve the predictive value of follicle-stimulating hormone or inhibin alone. CONCLUSION Age is a poorer predictor than pretreatment basal follicle-stimulating hormone and inhibin levels for ovarian response in in vitro fertilization cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment. Basal follicle-stimulating hormone and inhibin have similar predictive properties and could therefore be used interchangeably.

The effect of hormone replacement therapy on bone mass in patients with ovarian failure due to bone marrow transplantation

BACKGROUND Long permanent remissions in malignant hematopoietic disorders can often be achieved by autologous bone marrow transplantation (ABMT) or by allogenic bone marrow transplantation (BMT). Previous studies have shown that such therapies may induce osteoporosis due to iatrogenic ovarian failure. The administration of hormone replacement therapy (HRT) in these women could prevent the adverse effects of long-term ovarian failure without remarkable side effects. The aim of this study was to evaluate how the bone mass is affected by HRT in patients undergoing ABMT or BMT adjusting the results for age, weight, and height. SUBJECTS AND METHODS Thirteen women with previous ABMT/BMT were treated with a standard dose (0.625 mg/day) of conjugated equine estrogen (CEE) or with 50 micrograms/day of 17-beta-estradiol in transdermal therapeutic systems (TTS) plus 5 mg/day of medroxyprogesterone acetate sequentially added to the last 12 days of estrogen therapy. Bone mass was measured prior to and 12 months following HRT. Blood samples were collected before therapy and during the 6th and 12th treatment months. RESULTS The mean time elapsed between bone transplantation and HRT initiation was 13.0 months (range 3-26 months). Before treatment nine patients were osteopenic and after HRT bone mass increased in all cases. Following ABMT/BMT, hepatic hyperenzymemia was detected in three patients. After 6 and 12 months of treatment no significant changes were observed in hepatic enzymes. CONCLUSION Although hepatic hyperenzymemia is commonly considered as a contraindication for HRT, our results suggest that HRT is safe for these patients and that such therapy should be initiated after transplantation in women to prevent adverse effects of long-term ovarian failure.

Ovarian responses to recombinant FSH or HMG in normogonadotrophic women following pituitary desensitization by a depot GnRH agonist for assisted reproduction

At present, there is considerable debate about the utility of supplemental LH in assisted reproduction treatment. In order to explore this, the present authors used a depot gonadotrophin-releasing hormone agonist (GnRHa) protocol combined with recombinant human FSH (rhFSH) or human menopausal gonadotrophin (HMG) in patients undergoing intracytoplasmic sperm injection (ICSI). The response to either rhFSH (75 IU FSH/ampoule; group rhFSH, 25 patients) or HMG (75 IU FSH and 75 IU LH/ampoule; group HMG, 25 patients) was compared in normo-ovulatory women suppressed with a depot triptorelin injection and candidates for ICSI. A fixed regimen of 150 IU rhFSH or HMG was administered in the first 14 days of treatment. Treatment was monitored with transvaginal pelvic ultrasonographic scans and serum measurement of FSH, LH, oestradiol, androstenedione, testosterone, progesterone, inhibin A, inhibin B and human chorionic gonadotrophin (HCG) at 2-day intervals. Although oestradiol serum concentrations on the day of HCG injection were similar, both the duration of treatment and the per cycle gonadotrophin dose were lower in group HMG. In the initial 16 days of gonadotrophin treatment, the area under the curve (AUC) of LH, oestradiol, androstenedione and inhibin B were higher in group HMG; no differences were seen for the remaining hormones measured, including the inhibin B:inhibin A ratio. The dynamics of ovarian follicle development during gonadotrophin treatment were similar in both study groups, but there were more leading follicles (>17 mm in diameter) on the day of HCG injection in the rhFSH group. The number of oocytes, mature oocytes and good quality zygotes and embryos obtained were significantly increased in the rhFSH group. It is concluded that in IVF patients undergoing pituitary desensitization with a depot agonist preparation, supplemental LH may be required in terms of treatment duration and gonadotrophin consumption. However, both oocyte, embryo yield and quality were significantly higher with the use of rhFSH.

Dehydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency

Forty-four infertile patients with inadequate luteal phase histologically documented in at least two separate cycles and normal plasma levels of progesterone (P), estradiol (E2), and prolactin (PRL) were entered into treatment plans on a random basis involving at least 3 months of each of the following: P vaginal suppositories, dehydrogesterone, and no treatment. Success rates were similar for P (62.5%) and dehydrogesterone (68.7%), based on a corrected endometrial defect during the fourth treated cycle or when a term pregnancy was achieved. However, these figures are significantly different (P less than 0.001) when compared with 16.6% of the control group. In ten additional infertile patients with normal luteal function as assessed by endometrial histologic study and hormone measurements, a second biopsy was performed in a consecutive cycle under dehydrogesterone administration. In no case was the normal secretory pattern impaired. It is concluded that (1) both P and dehydrogesterone can be used to advantage in the treatment of luteal phase defects, and (2) therapy with dehydrogesterone does not alter the normal pattern of endometrial secretion.

The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction.

Purpose: The purpose of this prospective, randomized study was to compare ovarian response and oocyte and embryo yields in women undergoing ovulation induction for IVF/ICSI using recombinant human FSH (rhFSH) alone or in combination with recombinant human LH (rhLH).Methods: Patients were randomized to receive rhFSH alone (group F; n = 13) or rhFSH + rhLH (group L; n = 15). rhFSH was administered according to a step-down protocol; patients assigned to group L received rhLH at a fixed dose of 75 IU (1 ampoule) throughout the treatment period.Results: The total dose of rhFSH, number of growing follicles, and serum concentrations of estradiol (E2) on the day of hCG administration were similar in both treatment groups. However, the percentage of metaphase II oocytes and fertilization rate were significantly higher in group F than in group L. The lower fertilization rates associated with rhLH were also seen in a subgroup of patients from group L who had undergone a previous ART cycle stimulated with FSH only and thus acted as their own controls. However, when in vitro fertilization (IVF) and intracytoplasmic sperm injection cycles were considered separately, differences in fertilization rates were statistically significant only for oocytes treated by conventional IVF.Conclusions: This study shows that the addition of recombinant LH to recombinant FSH in pituitary-suppressed women undergoing ART does not improve the ovarian response and even may have a negative impact on oocyte maturation and fertilization.