Postmenopausal estrogen therapy, 1995.

Estrogen therapy offers women important benefits, including the potential prolongation of life by prevention of coronary heart disease (CHD) and osteoporotic fractures, and improvement of life by prevention of menopausal symptoms. Not all women can accept the potential side effects and risks, however, which include uterine bleeding, cystic mastitis, fluid retention, and increased risk of uterine cancer and breast cancer. Thus, the benefits and risks must be patiently weighed for each individual, and the alternatives of no treatment or other treatment should be clear. We review here the pertinent information that now makes these decisions quite sound.

Inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates nocturnal melatonin secretion in humans.

The catecholamine dopamine (D) is involved in the regulation of LH and PRL secretion, whereas a dysregulated noradrenergic system may contribute significantly to symptoms encountered in affective disorders. This explains the attraction of using alpha-methyl-para-tyrosine (AMPT) in neuroendocrine and psychiatric research, as it inhibits both neurotransmitters. PRL has been used as a marker of the effectiveness of AMPT in blocking D function, but no good marker for the effectiveness of AMPT in blocking norepinephrine (NE) is available. The purpose of this study was to determine whether melatonin (M) might serve as such a marker, as its production and secretion are regulated by NE. Seven subjects were given either AMPT or promethazine, which does not alter M secretion, in a randomized, double blind fashion, and 24-h M secretion was studied. Two-way analysis of variance revealed a significant difference in M secretion (F = 13.2; df = 17,102; P = 0.0013), with the following time points being different: 22, 23, 24, 1, 2, 3, 4, 5, and 6 h. Also, 24-h urinary 6-sulfatoxymelatonin excretion correlated highly with 24-h M secretion, expressed as the area under the curve in the AMPT experiment (r = 0.93; P = 0.002), which indicates that AMPT does not alter the metabolism of M. These results demonstrate for the first time that AMPT significantly attenuates nocturnal M secretion. It is concluded that M is a good marker for characterizing the effectiveness of AMPT in inhibiting sympathetic NE activity.

Mechanism of renal calcium conservation with estrogen replacement therapy in women in early postmenopause--a clinical research center study.

To assess the mechanism by which estrogen replacement therapy (ERT) enhances renal calcium conservation in perimenopausal women, we studied 18 normal women in early postmenopause before and after 6 months of ERT (cyclic treatment with transdermal estradiol at 100 micrograms/day and medroxyprogesterone acetate at 10 mg/day for the first 12 days of each cycle). The changes after ERT were: serum ionized calcium and ultrafiltrable calcium, no change; serum intact PTH, 38.2% increase (P < 0.0001); serum 1,25-dihydroxyvitamin D, 23.8% increase (P < 0.0001); urinary calcium excretion, 33.3% decrease (P < 0.001); and deoxypyridinoline (a marker for bone resorption), 19.5% decrease (P < 0.0001). Also, ERT increased tubular reabsorption of calcium (TRCa; 97.6% +/- 0.2% to 98.7% +/- 0.1%; P < 0.0001), and this increase correlated with that in serum PTH (r = 0.49; P < 0.05). After the infusion of human PTH-(1-34), the TRCa maximum was greater after ERT than at baseline (99.4% +/- 0.1% vs. 99.0% +/- 0.1%; P < 0.0001), resulting in decreased calcium excretion (0.9 +/- 0.20 vs. 1.43 +/- 0.20 mumol/dL glomerular filtrate; P < 0.001). Thus, in early postmenopause, the major mechanism of increased renal calcium conservation after ERT is an increase in TRCa due to an increase in serum PTH because of estrogen-induced inhibition of bone resorption. However, ERT also may directly increase the TRCa maximum in response to PTH.

Ectopic pregnancy: current evaluation and treatment.

During the past 20 years, the diagnosis and treatment of ectopic pregnancy have improved considerably. With the current diagnostic modalities, patients at risk for ectopic pregnancy can be followed expectantly, and the diagnosis can be made within a few days of the time of anticipated menses. An enhanced understanding of the varied clinical course of ectopic pregnancy has been gained in the process, and greater individualization of patient care has been possible. Patients with spontaneous tubal abortion are being identified, and they may be better served by observation. The precise role and limitations of pharmacologic agents and the new surgical procedures are still being determined, but the ultimate goal with use of these modalities is an improved potential for fertility.

Endometriosis: current management.

OBJECTIVE: To review the clinical features, theories of pathogenesis, and current treatment of endometriosis-associated pain and infertility. DESIGN: We review the manifestation of endometriosis and the possible mechanisms that lead to its symptoms, examine the efficacy of current therapeutic options for pelvic pain and infertility, and provide specific recommendations for treatment based on the current literature. MATERIAL AND METHODS: Endometriosis is the presence of hormonally responsive endometrial tissue occurring outside the uterine cavity. This condition may be asymptomatic but is often found in association with pelvic pain or infertility (or both). The precise pathogenesis has not been clearly established but likely involves retrograde menstruation with subsequent seeding of endometrial glands at extrauterine sites. The definitive diagnosis and staging of endometriosis are performed by laparoscopy. Various strategies have been used to treat endometriosis including expectant, medical, surgical, and combination management. RESULTS: The efficacy of treatment varies for pelvic pain and infertility. Endometriosis-associated pain may respond to both medical and surgical management. The use of medical therapy for endometriosis-associated infertility is not supported by current studies. Surgical management of infertility may be efficacious when pelvic anatomy is distorted because of endometriosis. The use of superovulation strategies and in vitro fertilization has been shown to be effective in overcoming endometriosis-associated infertility. CONCLUSION: Pelvic pain and infertility in the presence of endometriosis necessitate individualization of therapy to achieve treatment goals. Neither medical nor surgical management is efficacious in all circumstances. As a better understanding of the pathogenesis of endometriosis evolves, treatment of this perplexing condition will probably continue to improve.

Relative value of transdermal and oral estrogen therapy in various clinical situations.

OBJECTIVE: In this study, we reviewed the comparative effectiveness of transdermal and oral estrogen therapy in various groups of women. DESIGN: On the basis of published data and personal clinical experience, we compiled recommendations for use of the various modes of estrogen replacement therapy. MATERIAL AND METHODS: The use of injectable estrogen or implantable estrogen pellets can no longer be recommended because of their expense, inconvenience, and unphysiologic pattern of serum estrogen response. The two main estrogen preparations currently used in the United States--orally administered conjugated estrogens and transdermally administered estradiol--undergo different metabolism, and these processes are reflected in differing levels of circulating hormones and hepatic by-products, including blood clotting factors, binding proteins, renin substrate, and apolipoproteins, and in varied composition of the bile. RESULTS: At least theoretically, transdermal estrogen therapy might be more beneficial than oral estrogen therapy for women who smoke cigarettes or who have migraine headaches, hypertriglyceridemia, hepatobiliary disorders, fibrocystic breast disease, or a history of thromboembolism. In contrast, women with hypercholesterolemia might respond better to oral than to transdermal estrogen therapy. CONCLUSION: Additional properly designed clinical studies are necessary before these recommendations for estrogen replacement therapy can be validated or refuted.

Estrogen replacement therapy: current recommendations.

Estrogen replacement therapy is effective for the prevention and treatment of postmenopausal osteoporosis and should be offered to all women at high risk for osteoporosis. Such therapy is particularly beneficial for prevention of spinal compression fractures; in addition, it alleviates menopausal symptoms (hot flushes, genitourinary symptoms, and changes in mood). In each patient, these benefits must be weighted against the potential risks of endometrial hyperplasia and carcinoma, breast tenderness, hypertension, vascular headaches, and the inconvenience of menstrual bleeding if the uterus is intact. The risk of endometrial cancer associated with estrogen replacement therapy can be considerably reduced by the addition of a progestin, and other side effects can be diminished or eliminated by use of the new transdermal estrogen preparations. Thus, estrogen replacement therapy should be considered in all women who have experienced natural or surgically induced menopause, and it is advisable in women who have osteoporosis or an increased risk for this disorder and no contra-indications to its use. Estrogen replacement therapy should be instituted as soon after menopause as possible and seems to be well tolerated until at least 75 years of age.

Effects of long-term transdermal administration of estradiol on serum lipids.

OBJECTIVE: To evaluate the effect of three different dosages of transdermally administered 17beta-estradiol on serum lipoproteins in women who had recently experienced surgical menopause. MATERIAL AND METHODS: We undertook a 2-year, randomized, double-blind, placebo-controlled study in which 126 subjects were recruited and stratified by age, and 93 patients completed the protocol. Serum lipoproteins were assessed before initiation of treatment and after 12 and 24 months of therapy with 0.025, 0.05, or 0.1 mg of estradiol daily. RESULTS: Total serum cholesterol and low-density lipoprotein cholesterol showed dose-dependent decreases that reached statistical significance after 2 years of treatment with transdermally administered estradiol. CONCLUSION: This study confirms that transdermally administered 17beta-estradiol has a modest beneficial effect on serum lipoproteins, with decreased levels of total cholesterol and low-density lipoprotein cholesterol.

Parathyroid hormone-related peptide in lactation and in umbilical cord blood.

Parathyroid hormone-related peptide (PTHrP) is expressed in lactating rat mammary glands after suckling, as a result of increases in prolactin rather than suckling per se. In addition, PTHrP produced in the fetal parathyroid glands and placenta may be responsible for stimulation of placental calcium transport. In the current study, we used a radioimmunoassay for human PTHrP to measure levels of the peptide in (1) human breast milk, cow's milk, and two infant formulas; (2) sequential plasma samples in prepartum and postpartum lactating women; (3) women with pathologic hyperprolactinemia; and (4) human umbilical cord blood. In normal subjects, plasma PTHrP levels ranged from less than 2 to 5 pmol/liter. In contrast, human breast milk contained substantially increased levels of immunoreactive PTHrP. Similar elevations were found in cow's milk and in one infant formula. Column chromatography of breast milk demonstrated that PTHrP immunoreactivity included a region of adenylate cyclase stimulating activity, consistent with the presence of biologically active PTHrP. Plasma prepartum PTHrP values did not differ from corresponding postpartum values in lactating women. Women with hyperprolactinemia had a mean plasma PTHrP value in the high-normal range. Umbilical cord blood had considerably suppressed parathyroid hormone values but PTHrP levels that were indistinguishable from those in normal human plasma. Thus, PTHrP is present in high concentrations in breast milk but apparently does not gain access to the maternal circulation in significant amounts. In addition, women with pathologic hyperprolactinemia seem not to have increased levels of circulating PTHrP.(ABSTRACT TRUNCATED AT 250 WORDS)

The impact of gender on alpha-methyl-para-tyrosine mediated changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion.

Prolactin (PRL) and melatonin (ML) secretion are mediated by dopamine (DA) and norepinephrine (NE), respectively. Alpha-methyl-para-tyrosine (AMPT) inhibits the production of CNS catecholamines (CA). The purpose of the study is to determine: (1) if AMPT inhibition of ML has the same gender-dependent effect as on PRL secretion; (2) if there is a post AMPT-induced NE depletion mood change in men and/or women. In a randomized, double-blind cross-over fashion, five healthy young males and five females were either given five doses of AMPT 1 g (active) or promethazine 50 mg (placebo) over a 28 h period, separated by 4-6 weeks. The PRL and ML concentrations were collected at regular intervals via an indwelling venous catheter and concurrently, two 12 h urinary 6-hydroxymelatonin sulfate (6-MS) measurements were made. Mood and anxiety states of subjects at baseline and post drug were assessed with appropriate rating scales at regular intervals. Light exposure beginning at dusk and lasting until dawn was controlled to no more than 200 lux during all phases of the study. The PRL secretion showed a significant interaction of drug x time (p = .0001) in women and a non-significant trend (p = .056) in men. No difference in PRL secretion was found between the two genders in the placebo condition, whereas the PRL secretion was significantly higher in the AMPT condition in women when compared to men (df 17,119, F = 1.9, p = .021). Total 24 h urinary 6-MS secretion highly correlated with ML secretion expressed as area under the curve (AUC) during both active and placebo experiments (r = 0.8, p < .01) and (r = 0.86, p < or = .01), respectively. The ANOVA reveals a significant interaction of drug x time for 6-SM excretion. There was no gender difference in AMPT suppression of 6-MS excretion. No mood changes were detected in men or women. We conclude that urinary 6-MS is a reliable indirect measure of the degree of AMPT-induced decrease in CNS NE activity as part of overall AMPT-induced reduction of central catecholamine activities. The pre and post AMPT-induced changes in 6-MS are not gender dependent, dissimilar to the AMPT-induced changes in PRL secretion. Therefore, 6-MS, in addition to PRL, should be measured when applying the AMPT paradigm in future research.

Dextran 70 embolization. Another cause of pulmonary hemorrhage, coagulopathy, and rhabdomyolysis.

Thirty-two percent dextran 70 is a highly viscous polysaccharide liquid used for uterine distention during hysteroscopy. Although generally safe, this agent has been recognized recently to cause noncardiogenic pulmonary edema, renal insufficiency, and intravascular coagulopathy. We report a case of acute 32 percent dextran 70 embolization, associated with intravascular coagulopathy, bilateral lung infiltrates, and rhabdomyolysis, recognized initially by hemoptysis and pleuritic chest pain while the patient was in the recovery room following a hysteroscopic procedure. Pulmonary, anesthesiology, and critical care physicians should be aware of these potential complications of hysteroscopic surgery.

Pregnancy-associated major basic protein in amniotic fluid.

The pregnancy-associated major basic protein, a protein elevated in the sera of all pregnant women, is virtually identical to the eosinophil granule major basic protein. To determine whether pregnancy-associated major basic protein is present in amniotic fluid, we examined samples from both early and late gestation by a double antibody radioimmunoassay. A total of 112 amniotic fluids were tested and all but three contained levels of pregnancy-associated major basic protein greater than 400 ng/ml. Amniotic fluid pregnancy-associated major basic protein antigenic activity was immunochemically identical to that of the eosinophil granule major basic protein and also had identical physicochemical properties such as heat stability and the need for reduction and alkylation. Although the majority of amniotic fluid samples (90 of 112) were obtained from healthy women with normal gestations, the remaining 21 amniotic fluid samples were from women with Rh sensitization and from one gestation complicated by intrauterine growth retardation.

Beta-human chorionic gonadotropin, progesterone, and aqueous dynamics during pregnancy.

OBJECTIVE: To determine whether the altered hormonal milieu of pregnancy is associated with changes in the dynamics of aqueous humor formation and drainage. DESIGN: Nineteen women were studied during each trimester of a single pregnancy and post partum. Measures of aqueous dynamics included intraocular pressure, aqueous flow, facility of outflow, aqueous flare, and corneal thickness. RESULTS: Pregnancy was associated with relatively lower intraocular pressure, reduced aqueous flare, increased corneal thickness, and increased aqueous outflow facility. Aqueous flow was unchanged. The progesterone level increased during pregnancy and decreased during the postpartum period. The beta-human chorionic gonadotropin level was highest during the first trimester. The progesterone level, but not the beta-human chorionic gonadotropin level, was correlated with intraocular pressure, aqueous flare, and corneal thickness. The change in aqueous outflow facility that accompanied pregnancy could not be correlated directly to changes in beta-human chorionic gonadotropin or progesterone concentrations. CONCLUSIONS: Aqueous flow remains constant during and after pregnancy, but intraocular pressure decreases during pregnancy due to an increase in the outflow facility. The changes in aqueous dynamics are consistent with the hypothesis that excess progesterone during pregnancy blocks the ocular hypertensive effect of endogenous corticosteroids. However, we were unable to find a statistically significant correlation when a direct comparison between the observed changes in outflow facility and the observed changes in the progesterone level was made, perhaps because of intersubject variability of these changes. The changes in intraocular pressure and outflow facility could have been due to one of many other changes in pregnancy that were not measured.

Endometrial adenocarcinoma associated with drug-induced hyperprolactinemia.

A 54-year-old woman with hyperprolactinemia and amenorrhea that occurred with phenothiazine and tricyclic antidepressant use developed a stage IBG2 endometrial adenocarcinoma. This is believed to be the first case reported of endometrial carcinoma associated with drug-induced hyperprolactinemia.

Clinical application of nonselective assisted hatching of human embryos.

OBJECTIVE: To evaluate the effect of nonselective assisted hatching on pregnancy rate (PR) and to provide an alternative and simplified method for clinical application of assisted hatching. DESIGN: Retrospective analysis of clinical data. SETTING: Private infertility practice. PATIENT(S): Women from 258 consecutive stimulated IVF cycles. INTERVENTION(S): Assisted hatching was performed on each transferred embryo regardless of patient history, embryo morphology, or other selection criteria routinely applied to many IVF programs. MAIN OUTCOME MEASURE(S): Pregnancy, live birth, and implantation rates. RESULT(S): Of 258 consecutive patients who had nonselective assisted hatching, 109 (42%) had clinical pregnancies, with 93 (36%) live births and 178 (20%) embryos implanted. CONCLUSION(S): Nonselective assisted hatching resulted in an acceptable PR and provided an alternative and simplified method for clinical application of assisted hatching.

Ovulation induction with pulsatile gonadotropin-releasing hormone administration in patients with polycystic ovarian syndrome.

Gonadotropin-releasing hormone (0.025 microgram/kg) was administered intravenously in a pulsatile fashion to four subjects with polycystic ovary syndrome for a total of six cycles. Five of the six cycles culminated in ovulation, although in one course the response occurred too early to be attributed to the therapy alone. No pregnancies resulted. All luteal phases were of normal duration, but progesterone production as manifested by serum progesterone determination was deficient in some. If additional investigation confirms these preliminary findings, this form of therapy may offer a safe and economic alternative for anovulatory patients refractory to clomiphene citrate therapy. The response of the four subjects suggests that pulsatile gonadotropin-releasing hormone administration may override hypothalamic-pituitary dysfunction and result in ovulatory menstrual cycles.

Fertility after ectopic pregnancy.

OBJECTIVES: To compare pregnancy rates (PRs) after radical or conservative surgical treatment for tubal pregnancy over a 12.5-year interval (minimum of 3 years) and to assess the relative contribution of various risk factors to future fertility performance. DESIGN: A retrospective cohort study examining the influence of various risk factors on PRs with stepwise discriminant analysis using a jackknife-type validation program. PATIENTS: Eighty-eight Olmsted County, Minnesota, women who presented over a 10-year interval with their first ectopic pregnancy (EP), undergoing either radical or conservative surgery at laparotomy, who actively attempted conception after surgery and who were available for follow-up at Mayo Clinic. MAIN OUTCOME MEASURES: The primary end point for analysis was the occurrence of a livebirth or EP at 3 years of follow-up after the index EP. RESULTS: No difference in PR was identified in patients treated with radical or conservative surgery. Patients who underwent conservative surgery had a higher risk of subsequent EP. Patients with a prior history of infertility had significantly reduced fertility potential. CONCLUSIONS: Prior history of infertility was the most significant determinant for fertility potential after surgical treatment for EP. Patients with prior infertility had markedly impaired fertility after surgical treatment of EP, and outcome was not influenced by choice of surgical procedures. Patients without prior infertility had comparable encouraging fertility potential with both conservative and radical therapy. These findings have relevance for future management of infertility in affected patients.

A successful assisted reproductive technology satellite program.

A satellite program was implemented to provide IVF to interested infertile couples living in a five-state area. Thirty-six gynecologists were established as satellite sites after appropriate screening and training. No attempt was made to interchange reference serum specimens between laboratories. Patients were seen at Mayo Clinic for an initial consultation and did not return until the ovulatory dose of hCG was administered. There was no difference in cancellation, clinical pregnancy, and delivery rates between satellite and central unit monitored patients. Satellite monitoring decreases patient inconvenience and time away from home and the workplace without compromising cycle outcome.

Clinical application of intracytoplasmic sperm injection using in vitro cultured testicular spermatozoa obtained the day before egg retrieval.

OBJECTIVE: To study the effect of in vitro culture on the quality of human testicular sperm and the efficiency of intracytoplasmic sperm injection with in vitro cultured testicular sperm. DESIGN: Clinical study. SETTING: A private IVF center. PATIENT(S): Twenty consecutively seen IVF patients undergoing testicular biopsies for ICSI. INTERVENTION(S): The testicular specimens were cultured in vitro for 24 hours and the isolated spermatozoa were microinjected. MAIN OUTCOME MEASURE(S): Preincubation and postculture sperm motility, and fertilization, implantation, and pregnancy rates after intracytoplasmic sperm injection. RESULT(S): Motility increased from initial nonmotile or twitching sperm to free motile sperm in 18 of 20 cases. The injection of in vitro cultured testicular sperm resulted in a fertilization rate of 58%, an implantation rate of 20%, and a pregnancy rate of 45%. CONCLUSION(S): A testicular biopsy procedure can be performed the day before egg retrieval. Despite the low initial sperm quality, a high percentage of the prepared testicular sperm showed increased motility after 24 hours of culture. The injection of in vitro cultured testicular sperm into matured oocytes resulted in fertilization, implantation, and pregnancy rates comparable to those obtained with ejaculated sperm.

A comparison of post-thaw results between cryopreserved embryos derived from intracytoplasmic sperm injection and those from conventional IVF.

OBJECTIVE: To study the effect of freezing on early stage embryos derived from intracytoplasmic sperm injection (ICSI) or from IVF. DESIGN: Prospective, controlled clinical study. SETTING: Private IVF center. PATIENT(S): Sixty-seven consecutive patients undergoing frozen-thawed embryo transfer cycles. INTERVENTION(S): Early stage embryos were frozen, thawed, and transferred. MAIN OUTCOME MEASURE(S): Post-thaw survival, implantation and pregnancy rates. RESULT(S): We noted an 88% post-thaw survival rate, an 18% implantation rate, and a 52% pregnancy rate in the ICSI group and 81%, 11%, and 25%, respectively, with conventional fertilization. CONCLUSION(S): Early stage embryos (either zygote or 2-4 cells) derived from ICSI can be frozen with confidence and higher post-thaw survival and pregnancy rates can be achieved when compared with those from conventional IVF.