Recursos necesarios en la mejora de la salud pública en obstetricia y ginecología / Resources required for the improvement of public health in obstetrics and ginecology

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Los estrógenos como carcinógenos / Estrogens as carcinogens

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Ética del tratamiento hormonal sustitutivo de la menopausia con estrógenos y gestágenos / Ethics of hormone replacement therapy with estrogens and gestagens in menopause

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Bioética y reproducción asistida / Bioethics and assisted reproduction

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Consideraciones éticas sobre la cesárea. Comisión de Bioética de la SEGO / Ethical considerations on cesarean sections. Bioethics Committee of the Spanish Society of Obstetrics and Gynecology

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Treatment of cervical intraepithelial neoplasia in a prospective study comparing large-loop excision of the transformation zone, laser vaporization, and knife cone biopsy.

OBJECTIVE: Our aim was to compare cervical intraepithelial neoplasia (CIN) treatment results in the use of large-loop excision of the transformation zone (LLETZ), laser vaporization, and cold-knife cone biopsy. MATERIALS AND METHODS: We included in the study patients with CIN lesions diagnosed at the Hospital Universitario Materno-Infantil Vall d'Hebron and Hospital Clinic i Provincial de Barcelona, Barcelona, Spain, between March 1991 and March 1994. Patients with unsatisfactory colposcopy were excluded from the study. One hundred twenty-three patients were included in this study: 98 patients were compared for LLETZ treatment versus laser vaporization, and 69 CIN3 patients were compared for three treatments: LLETZ, laser vaporization, and knife cone biopsy. Patients were followed at 3-month intervals for at least 1 year. Follow-up included physical examination, cervical Papanicolaou (Pap) smear, cervical colposcopy, and a colposcopically guided biopsy when required. Treatment failure (persistence or recurrence) was defined by the presence of CIN confirmed histologically by a colposcopically guided biopsy. RESULTS: The mean age of patients was 34.1 years. The agreement between histology from the colposcopically guided biopsy and the surgical specimen was 60%, and the kappa coefficient was 40.7% (moderate agreement). Three cases of microinvasive carcinoma were diagnosed in patients whose initial diagnosis was CIN3 on colpobiopsy (4% of invasion in the initial CIN3 group of patients). In a comparison of LLETZ with laser treatment for all CIN grades, the unique independent prognostic factor for persistence-recurrence of the disease was the colposcopic size of the primary lesion (relative risk, 4.9; Cl, 1.33-18.45). CONCLUSIONS: We conclude that the LLETZ procedure for CIN treatment demonstrates an advantage over destructive methods for detection of occult microinvasive and invasive cancer. This process is a simple outpatient technique with the same failure as that of laser vaporization in all CIN grades. In the treatment of CIN3, cold-knife cone biopsy had better cure rates. Close follow-up is required in these patients, because of their risk of developing recurrent CIN or invasive carcinoma.

Circulating hormone levels in menopausal women receiving different hormone replacement therapy regimens. A comparison.

OBJECTIVE: To measure and compare plasma levels of sex hormones after the administration of different hormone replacement therapy (HRT) regimens. STUDY DESIGN: Ninety women with natural menopause were randomized into this comparative study. Eighty-five women completed one year of follow-up. Patients were randomly assigned to five groups. The first received 0.6 mg/d of conjugated equine estrogen (CEE) cyclically (n = 15). The second received 50 micrograms/d of transdermal estradiol (E2) cyclically (n = 17), and the third received 0.6 mg/d of CEE continuously (n = 17). All these groups also received 2.5 mg of medroxyprogesterone acetate (MPA) sequentially for the last 12 days of HRT, while the fourth therapy group received 0.625 mg/d of CEE and 2.5 mg/d of MPA continuously (n = 19). The fifth group constituted a treatment-free control group (n = 22). Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, estrone (E1), prolactin (PRL), testosterone (T), androstenedione (A4), dehydroepiandrosterone sulfate (DHEA-S) and sex hormone binding globulin (SHBG) were determined prior to HRT and during the last week of the 6th and 12th months of HRT, between days 21 and 24 of estrogen administration. RESULTS: After HRT we found decreases in FSH, LH and PRL levels, increases in E2, E1 and SHBG, and no modifications in T, A4 and DHEA-S plasma levels. There were no significant differences between the treatment groups in FSH, LH, E2, PRL, T, A4 or DHEA-S. E1 and SHBG were significantly higher in the groups with oral HRT. CONCLUSION: All the observed changes in hormone levels are to be expected after HRT except for the decrease in PRL levels. Finally, although MPA dosage was not the focus of the present study, our results suggest that the dosage of 2.5 mg/d of MPA in sequential regimens is clearly inadequate to protect the endometrium from hyperplastic changes.

Postmenopausal hormone replacement therapy with low-dose medroxyprogesterone acetate. Endometrium, plasma lipids, lipoproteins and apolipoproteins.

Several studies have demonstrated that the use of estrogens in postmenopausal women has a protective effect against cardiovascular disease; however, this beneficial effect may be counteracted when concomitant progestogens are administered. We investigated the influence of hormone replacement therapy (HRT) with lower doses of medroxyprogesterone acetate (MPA) (2.5 mg/d) on the endometrium and on the plasma levels of lipids, lipoproteins and apolipoproteins. All the studied HRT regimens induced favorable changes in the levels of plasma lipids, lipoproteins and apolipoproteins, which may play an important role in the prevention of cardiovascular disease. The dosage of 2.5 mg/d of MPA is clearly inadequate to protect the endometrium from hyperplastic changes with sequential regimens, but probably this dosage is safe when MPA is administered continuously.

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.

Effects of oophorectomy and hormone replacement therapy on pituitary-gonadal function.

The purpose of this study was to determine how oophorectomy and different hormone replacement therapy (HRT) regimens using low doses of medroxyprogesterone acetate (MPA, 2.5 mg/day) influence the pituitary-gonadal axis function. Ninety (90) women, who had had regular menses prior to surgery, completed a 1-year follow-up period. Patients were assigned to 5 groups. The first (n = 16) received 0.625 mg/day conjugated equine oestrogens (CEE) cyclically, the second (n = 20) 50 micrograms day transdermal oestradiol (E2) cyclically and the third (n = 15) 0.625 mg/day CEE continuously. These 3 groups also received 2.5 mg MPA sequentially for the last 12 days of HRT administration. The fourth group (n = 20) received 0.625 mg/day CEE and 2.5 mg/day of MPA continuously, while the fifth (n = 19) constituted a control group. After oophorectomy all patients showed increases in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and decreases in those of E2, oestrone (E1), prolactin (PRL), sex-hormone-binding globulin (SHBG), androstenedione (delta A4) and testosterone (T). No changes were detected in dehydroepiandrosterone sulphate (DHEA-S) levels. After HRT, decreases in FSH, LH and PRL levels and increases in those of E2, E1 and SHBG were observed, but no changes were seen in T, delta A4 or DHEA-S plasma levels. As the differences that were found cannot be attributed to the presence of ovaries, it is reasonable to assume that they were perhaps due to the treatment. All these changes, with the exception of a decrease in PRL levels, are therefore to be expected after HRT.

Effects of oophorectomy and hormone replacement therapy on plasma lipids.

The aim of this study was to determine the effects on plasma lipids and lipoproteins of oophorectomy and various hormone replacement therapy (HRT) delivery systems using low doses of medroxyprogesterone acetate (MPA, 2.5 mg/day). A total of 90 women completed the 1-year follow-up period. Patients were randomly assigned to five groups. The first (n = 16) received 0.625 mg/day conjugated equine oestrogens (CEE) cyclically, the second (n = 20) 50 micrograms/day transdermal oestradiol cyclically and the third (n = 15) 0.625 mg/day CEE continuously. These three groups also received 2.5 mg MPA sequentially for the last 12 days of HRT administration. The fourth group (n = 20) received 0.625 mg/day CEE and 2.5 mg/day MPA continuously, while the fifth (n = 19) constituted a treatment-free control group. After oophorectomy patients showed increases in low-density lipoprotein (LDL), apolipoprotein B and the atherogenic index, whereas after HRT patients exhibited falls in plasma LDL, apolipoprotein B and the atherogenic index and increases in high-density lipoprotein (HDL) and apolipoprotein A1. No significant changes in total cholesterol were observed after surgery or treatment and decreased levels of triglycerides were detected only in the transdermal treatment group.

Ovarian function, tubal viability and pregnancy after tubo-ovarian transplantation in the rabbit.

A rabbit model was developed for microsurgical en-bloc vascularized tubo-ovarian allograft. Transplantation of tube and ovary from donors to tubo-oophorectomized recipients was technically successful in 50 rabbits. After surgery, animals were randomly allocated into two groups: animals in group A received cyclosporine for immunosuppression; animals in group B did not receive immunosuppressive therapy. In group A, 16 animals survived the transplant procedure and six animals became pregnant (38%). No pregnancies were obtained among animals in group B. In group A, plasma concentrations of ovarian and pituitary hormones were similar to those found in non-transplanted animals. Our results show firstly that tubo-ovarian transplantation is technically feasible, and secondly that cyclosporine improves not only tubal viability but also ovarian function after transplantation.

Bone mineral density in surgically postmenopausal women receiving hormonal replacement therapy as assessed by dual photon absorptiometry.

A total of 118 postmenopausal women who had undergone hysterectomy and bilateral oophorectomy were invited to participate in this study. Patients were randomly allocated to one of four study groups which received, respectively, conjugated equine oestrogens (CEE) 0.625 mg/day over a 25-day cycle each month (n = 28); transdermal 17 beta-oestradiol 50 micrograms/day over a 24-day cycle each month (n = 28), CEE 0.625 mg/day every day of the month (n = 32) and no treatment the control group (n = 30). All the treated patients also received 2.5 mg/day medroxyprogesterone acetate sequentially for the last 12 days of each cycle. Dual photon absorptiometry was performed before therapy commenced and repeated after 1 year in all four groups. The three therapeutic regimens induced increases in bone mass, whereas a significant decrease was observed in the control group (P < 0.05).

Skin collagen changes related to age and hormone replacement therapy.

A total of 76 nulliparous women who had been hospitalized for minor operations, classified according to age group (by decade from 20s to 60s) and 118 postmenopausal women randomly allocated to one of four groups were studied. In all, 312 skin biopsies were taken from the lower abdomen at 0 and 12 months and the skin collagen changes noted. Collagen content decreased significantly with age beyond the 40s (P < 0.001) and after the menopause (P < 0.01). The decrease was preventable by the use of hormone replacement therapy. All the therapeutic regimens induced increases in skin collagen content, whereas in the control group a significant decrease was observed (P < 0.05).

The effect of hormone replacement therapy on postmenopausal bone loss.

Eighty-four postmenopausal women who were randomly allocated to one of four groups, completed a 1 year follow-up. The first group (n = 20) received 0.625 mg/day conjugated estrogens cyclically (CE; 25 days/month). The second (n = 23) received 0.625 mg/day of CE continuously, and the third (n = 17) received 50 micrograms/day of transdermal 17 beta-estradiol cyclically (24 days/month). All these groups also received 2.5 mg of medroxiprogesterone acetate sequentially for the last 12 days of hormone replacement therapy, while the fourth group (n = 24) constituted a treatment-free control group. Dual photon absorptiometry was carried out before therapy and was repeated after 1 year. Serum calcium, phosphate and osteocalcine levels, and the urinary calcium/creatinine and hydroxyproline/creatinine ratios, were measured prior to treatment and 6 and 12 months thereafter. All treatment groups showed an increase in bone mineral content. This increase was higher in the continuous CE treatment group (4.4%, P less than 0.05) and in transdermal group (7.1%, P less than 0.01). Concomitant biochemical effects at 6 and 12 months, reduction in urine calcium and hydroxyproline, reduction in blood calcium, phosphate and osteocalcine, were compatible with the observed effects on bone mineral.

Hormone replacement therapy and changes on pituitary function.

The aim of this study is to know how the pituitary function is affected by several delivery systems of estrogen replacement therapy. 116 menopausal women (54 natural and 62 surgical) were placed into three groups that received replacement therapy and in one control group. We determined prolactine (PRL), gonadotropins and 17 beta-estradiol (E2). We found a decrease in gonadotropin levels in treated patients with a natural menopause, and an increase in gonadotropin levels in the groups treated with conjugated estrogens in surgical menopausal women. 17 beta-E2 was found to be increased in all treated groups, mainly in the continuous therapy group (P less than 0.05). PRL was found to be decreased in patients treated with conjugated estrogens (oophorectomized and not oophorectomized) (P less than 0.05). Although these differences can not be attributed to the presence of the ovaries, we think that they may be the result of the treatment.

Endometrial cytosolic and nuclear progesterone receptors in the luteal phase defect.

Basal body temperature profiles, serial serum progesterone levels, and serial endometrial biopsies were studied in 15 infertile women during 21 ovulatory cycles. Ten cycles (in 9 women) demonstrated luteal phase defects (LPD), diagnosed by a histological lag in endometrial maturation, normal luteal phase length, and normal luteal phase serum progesterone levels. Both normal and LPD cycles had a maximum amount of endometrial cytosolic progesterone receptor (PgR) on days 13-15, with a significant decline thereafter. LPD cycles had significantly lower endometrial nuclear PgR concentrations than did normal cycles during the proliferative phase, but luteal phase endometrial nuclear PgR levels were similar in both groups. In 2 LPD women treated with dydrogesterone, normal endometrial maturation and a decline in endometrial cytosolic PgR concentrations in the late luteal phase were found. Therefore, with the exception of endometrial nuclear PgR concentrations during the proliferative phase, we found no evidence for a major abnormality in endometrial PgR levels in LPD cycles with a lag in endometrial histology.