Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women.

OBJECTIVE: To determine the effects of dietary inclusion of soy foods on clinical markers for cardiovascular disease (CVD) and osteoporosis in normal postmenopausal women. DESIGN: This was a single open-group prospective clinical intervention. Forty-two normal postmenopausal women consumed three daily servings for 12 consecutive weeks of whole soy foods containing approximately 60 mg/d of isoflavones. Blood and urine specimens were obtained at baseline and after 12 weeks of dietary intervention. RESULTS: Serum and urine levels of individual and total isoflavones increased significantly (7-19 fold, p < 0.001) from baseline. A significant increase (9.3%, p < 0.05) in the mean lag-time of low-density lipoprotein cholesterol oxidation was seen and was positively correlated with serum phytoestrogens (p < 0.05). Significant increases were found in mean levels of high-density lipoprotein cholesterol (HDLc) (3.7%, p < 0.05) and serum osteocalcin (10.2%, p < 0.025). Significant decreases were observed in total cholesterol:HDLc ratios (5.5%, p < 0.006) and mean urinary N-telopeptide excretion (13.9%, p < 0.02). Urinary excretion of total isoflavones was negatively correlated with very-low-density lipoprotein cholesterol, triglycerides, and total cholesterol:HDLc ratios (p < 0.04). No significant changes from baseline in HDLc peroxidation, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, bone-specific alkaline phosphatase, follicle-stimulating hormone, or estradiol levels were observed. CONCLUSIONS: Dietary inclusion of whole soy foods containing 60 mg/d of isoflavones results in significant serum levels of phytoestrogens and reductions in several key clinical risk factors for CVD and osteoporosis in normal postmenopausal women. Long-term, placebo-controlled clinical trials are needed to evaluate the effect of phytoestrogens on the clinical endpoints of CVD and osteoporosis in this population.

Low-dose esterified estrogens (0.3 mg/day): long-term and short-term effects on menopausal symptoms and quality of life in postmenopausal women.

OBJECTIVE: To study the impact of low-dose unopposed esterified estrogens on menopausal symptoms and quality of life. METHODS: In a long-term, 2-year, randomized, double-blind, placebo-controlled study, 204 postmenopausal women were treated with esterified estrogens 0.3 mg daily or placebo. Menopausal symptoms were assessed with a modified Kupperman index at baseline, 3, 6 and thereafter every 6 months. In a second 12-week, open-label, short-term pilot study, 25 postmenopausal women with moderate to severe vasomotor symptoms were treated with esterified estrogens 0.3 mg daily for 12 weeks. Vasomotor symptoms and quality of life were assessed using the Greene scale and Quality of Life Menopause Scale (QUALMS). RESULTS: In the long-term study, significant (p < 0.05) reductions in total symptom scores were observed at each time point with esterified estrogens compared with placebo. Somatic symptom scores (hot flushes, night sweats, vaginal dryness) decreased significantly (p < 0.01) in patients treated with esterified estrogens 0.3 mg compared to baseline and placebo. In the short-term, open-label pilot study, the incidence of vasomotor symptoms was significantly (p < 0.01) reduced with esterified estrogens 0.3 mg from week 4 until the study end. Significant (p < 0.05) improvements versus baseline were seen in the somatic and vasomotor/sleep domains and in the total quality-of-life score. CONCLUSIONS: Esterified estrogens 0.3 mg given daily provide adequate menopausal symptom relief and improved quality of life in postmenopausal women.

Isoflavones and postmenopausal bone health: a viable alternative to estrogen therapy?

OBJECTIVE: The rapidly growing postmenopausal population in the United States, and this population's high incidence and prevalence of osteoporosis and related morbidity and mortality herald an enormous public health burden for the coming decades. Estrogen replacement has been the mainstay of therapy for the prevention and treatment of osteoporosis in this estrogen-deficient population. However, long-term compliance with estrogen therapy generally is poor, and there are numerous concerns regarding its safety. The phytoestrogens are nonsteroidal plant-derived compounds that exhibit estrogenic activity at several sites. The isoflavones are one class of phytoestrogens derived largely from soy-based products. International popularity for menopausal therapy regimens containing isoflavones is growing rapidly. In this article, we review the existing data on isoflavones and postmenopausal bone health. DESIGN: A review of interventional trials examining isoflavones and bone in animals and humans. RESULTS: The data point to a reduction in bone resorption resulting from isoflavone/ipriflavone intake. CONCLUSIONS: The data on naturally occurring isoflavones are very limited but suggest that including them in the diet results in reduction in bone resorption caused by estrogen deficiency. The extensive data on ipriflavone, a synthetic isoflavone derivative, suggest that it is a useful and safe alternative to estrogen therapy in treating existing low bone mass or osteoporosis in postmenopausal women. Further studies are warranted to examine the utility of ipriflavone as a preventive agent, as well as the clinical efficacy of the naturally occurring isoflavones.

Following patients under treatment for hyperprolactinemia.

Management of patients receiving treatment for hyperprolactinemia depends on a few specific parameters: whether the patient has no pituitary lesion, a pituitary microadenoma or a pituitary macroadenoma. In each of these categories, management will differ depending on whether the patient desires to become pregnant. Some patients with hyperprolactinemia who are asymptomatic may be managed expectantly, with periodic measurement of serum prolactin levels and careful monitoring for emergence of symptoms. In the vast majority of cases, treatment with a dopamine agonist is appropriate and effective. If pregnancy is desired, efforts should be made to time it carefully and to discontinue the drug as soon as a pregnancy test is positive. Only patients with macroadenomas who do not respond adequately to medical therapy and show signs of a cranial mass effect from the lesion should be referred for neurosurgical evaluation.

Combination oral contraceptives.

PIP: Although an individual assessment of the risks and benefits is always essential, combined, low-dose oral contraceptives (OCs) are an effective method of fertility control, even for women with chronic medical problems. In addition to contraception, therapeutic uses of combined OCs include acne, anovulatory uterine bleeding, control of bleeding with blood dyscrasias, dysmenorrhea, endometriosis, hirsutism, hypothalamic amenorrhea, ovarian hormone replacement, polycystic ovarian syndrome, premenstrual syndrome, and recurrent functional ovarian cysts. This article presents guidelines for clinicians on the selection of combined OC users, counseling, contraindications, and management of adverse effects. It further outlines general considerations for the prescription of combined OCs to women with hypertension, diabetes mellitus, migraine headaches, and epilepsy.^ieng

Success of donor oocyte in in vitro fertilization-embryo transfer in recipients with and without premature ovarian failure.

OBJECTIVE: To compare the effectiveness of donor oocyte in IVF-ET in patients with premature ovarian failure (POF) versus those (non-POF) with other indications for donor oocyte IVF-ET. DESIGN: Retrospective comparative clinical study. SETTING: University-based IVF-ET facility. PATIENTS: Eighty-six donor oocyte IVF-ET cycles from 32 POF patients (39 cycles) and 38 non-POF patients (47 cycles). INTERVENTIONS: Fertile oocyte donors, age 19 to 38 years, were given luteal phase GnRH agonist, gonadotropins, and HCG. Recipients were given transdermal 17 beta-E2 and P in oil. MAIN OUTCOME MEASURES: Donor and recipient age, characteristics of controlled ovarian hyperstimulation, oocytes retrieved, embryos frozen and transferred, and percentage with male factor infertility, fertilization rate, implantation rate, and clinical pregnancy rate (PR) per cycle and per transfer. RESULTS: Given limitations of sample size, there were no detectable differences in clinical PR per cycle and per transfer, fertilization rate, and implantation rate between POF and non-POF groups despite recognizable differences in recipient age and degree of male factor infertility. CONCLUSIONS: Donor oocyte IVF-ET success rates were not different in patients with and without POF. Age-related changes in oocyte quality, rather than uterine senescence, is a major factor for the age-related decline in fertility.

Expectant management of a hypothalamic mass: a case report.

BACKGROUND: Although hypothalamic masses are usually benign, they may infiltrate hypothalamic-pituitary structures, resulting in multiple endocrinopathies, optic nerve damage, increased intracranial pressure, and death. Controversy exists regarding proper management. CASE: A young woman with a hypothalamic mass suggestive of craniopharyngioma presented with pubertal delay and hypothalamic amenorrhea without evidence of progression over 4 years. She was given sex steroid replacement and observed, thereby avoiding surgery or radiotherapy. CONCLUSION: Large hypothalamic masses may present with minimal signs and symptoms that are not life threatening. Without more serious symptoms, these can be managed expectantly to avoid the risks of panhypopituitarism, diabetes insipidus, vision loss, and cerebrovascular accidents resulting from any therapy.

Unanswered questions in hormonal replacement therapy.

This review addresses many of the unanswered questions existing relative to the use of exogenous estrogens and progestins in postmenopausal women (PMW). The literature in the field is reviewed and summarized, with a particular effort to identify key questions of major concern. The effect of selection bias on conclusions reached from retrospective studies involving hormone replacement therapy (HRT) has not been examined. Less is actually known about the effects of progestins than estrogens. Many of the endocrine changes that occur with aging remain poorly defined. Effects of estrogens and progestins on the breast and on breast cancer are unclear. Estrogens have recognized beneficial effects and progestins have detrimental effects on lipoprotein metabolism. Estrogens also have direct effects on the vasculature and may impact on cardiovascular risk in other ways. Although estrogens are the only agents known to eliminate hot flushes, the mechanism by which flushes arise is not known. Estrogens may have ameliorating effects on mood and behavior and may improve dementia, but research in this area has been limited to date. Lastly, the preferred estrogens and progestins, their dosages and routes of administration, remain to be more completely defined.

Effect of human prolactin administration on gonadotropin and thyrotropin secretion in normal men.

To test the hypothesis that PRL is able to feedback negatively on its own secretion (short-loop feedback) in humans via augmentation of the turnover of tuberoinfundibular dopamine (TIDA), the effects of the administration of purified hPRL on endogenous LH, FSH and TSH were assessed. Purified hPRL, given in an i.v. loading dose of 90 micrograms followed by a continuous infusion of 1.39 micrograms/min to 4 normal male volunteers resulted in a tripling of PRL levels (10.5 +/- 1.9 micrograms/L increasing to 30.9 +/- 3.6 micrograms/L) at the end of 90 min. There were no changes in LH, FSH or TSH levels, however, during or following the infusion. Purified hPRL was also given in 1 and 8 micrograms/kg doses IM to 5 normal male volunteers. Although PRL levels did not rise significantly with the 1 microgram/kg dose, levels almost doubled with the 8 micrograms/kg dose (9.5 +/- 2.2 micrograms/L increasing to 17.4 +/- 1.5 micrograms/L). Again, LH, FSH and TSH levels did not change significantly over the three hour period of sampling with either dose. In conclusion, in this study we found that a 2-3 fold increase of circulating PRL levels maintained for 1.5-3 h exerted no apparent effects on the secretion of endogenous LH, FSH and TSH. This study provides direct evidence against the existence of a short-loop feedback occurring via TIDA activation in humans over this time interval but does not rule out the possibility that such feedback may occur with more prolonged states of hyperprolactinemia or via other mechanisms or the possibility of an effect on the hypothalamic pulse generator.

Contraceptive methods for women with neurologic disorders.

Sex steroids in oral contraceptives exert several effects on the central nervous system and are therefore of concern when used by neurologically compromised women. In general, oral contraceptives do not aggravate epileptic seizures and are not contraindicated in cases of tension headache. Oral contraceptives can be used in cases of migraine without focal neurologic symptoms as long as headache symptoms do not worsen. Levels of sex steroids can be diminished through enzyme induction by antiepileptic drugs, giving rise to the possibility of contraceptive failure and exposure of the fetus to the teratogenic properties of antiseizure medications. Women with common migraine (without focal neurologic symptoms) who are taking oral contraceptives should be monitored for possible exacerbation of their symptoms. Women who do experience worsening of headache symptomatology when taking the pill should consider alternate means of contraception.

PIP: A leading patient complaint is headaches which tend to occur more often in women than men. Nonvascular headache is the most common and is caused by tension or muscle contraction. Oral contraceptives (OCs) do not affect nonvascular headaches. They can also be safely used in women who experience common migraines whose symptoms do not become more severe or frequent during OC use. On the other hand, women who have classic migraine (headache accompanied by focal neurologic symptoms) or common migraine with symptoms becoming more severe or frequent during OC use should discontinue OC use. Instead, they should use a barrier method or the IUD. Estradiol treatment appears to be effective in treating menstrual migraine. Since the data are inconclusive about the effect of OCs on young women who have experienced a stroke or transient ischemic attacks, it would be best for them to use a barrier method. Most antiepileptic drugs (phenobarbital, phenytoin, paramethadione, and carbamazepine) cause enzyme induction which may be linked to decreased levels of estrogen and increases in irregular bleeding, thereby increasing the likelihood of an epileptic OC user becoming pregnant. Possible contraceptive failure exposes a developing fetus to the teratogenic properties of the antiepileptic drugs. Thus, physicians should prescribe OCs with 50 mcg of ethinyl estradiol rather than 35 mcg ethinyl estradiol. Epileptic women can also use Depo-Provera, because it is not only effective in preventing pregnancy but reduces seizure frequency. It is important for any contraceptive method chosen for epileptic women to be effective because pregnancy intensifies seizures which in turn can damage the mother and/or fetus and cause neonatal distress.

Antiestrogenic potency of toremifene and tamoxifen in postmenopausal women.

In this nonblinded, controlled multicenter trial, postmenopausal women were randomly assigned to receive graded doses of toremifene and tamoxifen or no antiestrogen to assess dose-response levels and evaluation methodology. For standardization, transdermal estradiol (Estraderm-Ciba Geigy) was applied to all women for 38 days. The antiestrogens were added on days 29-38. For control and all treatment groups, there were no significant changes in serum chemistries or serum hormone levels, nor were there differences in adverse effects. The use of continuous estradiol precluded any meaningful assessment of the estrogenicity of tamoxifen or toremifene. As measured by vaginal superficial cytologic cell count changes, the antiestrogenic activity of toremifene doses ranging from 20 to 200 mg/day could not be distinguished from that of 20 mg/day of tamoxifen, the clinically recommended dose in North America.

Evidence of a corticotropin-releasing hormone pulse generator in the macaque hypothalamus.

The secretion of hormones from the hypothalamic-pituitary axis is, in general, characterized by an episodic pattern of release. In the adrenal axis, ACTH and cortisol levels in peripheral blood display irregularly pulsatile ultradian patterns that are superimposed on the well characterized circadian rhythm. While it is generally accepted that CRH is released from the hypothalamus in a similar manner, very few studies have actually examined the temporal release of CRH. To examine the temporal release of CRH directly, we have established an in vitro perifusion system using the hemisectioned macaque hypothalamus. Perifusate samples were collected at 10-min intervals for 20 h and assayed for CRH by RIA. In control animals, a very regular, pulsatile pattern of hormone release was present, with a pulse interval of 90 +/- 11 min. Although this interval closely approximates the average pulse interval of ACTH and cortisol in the human, the regular pattern revealed in our study has not been demonstrated previously in the adrenal axis in vivo and suggests that factors outside the hypothalamus play a major role in controlling adrenal hormone levels. When hypothalami were perifused with dexamethasone added to the culture medium, no change in pulsatile activity was detected, indicating that a site outside of the hypothalamus may function as the primary center of feedback inhibition by adrenal glucocorticoids in the central nervous system. Because the very regular pulses of CRH that we observed bear striking similarity to the circhoral pulses of GnRH, we speculate that CRH may play a more subordinate role in regulating the adrenal axis and that other releasing factors and/or feedback effects at the pituitary level may be more important in the generation of the irregularly pulsatile, circadian patterns of ACTH and cortisol seen in peripheral blood.

Hypergonadotropic forms of amenorrhea in young women.

Hypergonadotropic forms of amenorrhea in young women are many and varied, and the disorder is not nearly as uncommon as previously believed. It is likely that all physicians seeing women with amenorrhea will encounter this disorder. Careful evaluation is warranted to eliminate any associated autoimmune disorders. Because of the high likelihood of osteopenia in affected individuals, estrogen replacement therapy is warranted. Although pregnancy is possible in women with secondary hypergonadotropic amenorrhea, remarkably it most commonly occurs in women utilizing exogenous estrogen. Women desirous of achieving a pregnancy are best served by assisted reproductive technology utilizing donor oocytes. Success rates in such patients have been quite high. Thus, physicians today can counsel affected women that pregnancy is indeed possible, even in women with so-called "premature ovarian failure."

Depletion of luteal phase serum progesterone during constant infusion of cortisol phosphate in the cynomolgus monkey.

OBJECTIVE: To study the impact of chronic infusions of cortisol phosphate on ovarian function in the cynomolgus monkey. DESIGN: Cortisol phosphate at doses of 5 or 15 mg/d or saline were infused for periods of up to 8 weeks using subcutaneously implanted osmotic pumps. SETTING: Animals were maintained in the Center for Experimental Animal Resources, Northwestern University. MAIN OUTCOME MEASURES: Serum total and unbound cortisol concentrations, serum total and unbound progesterone (P) concentrations, urinary P metabolites. RESULTS: Mean increases in serum cortisol of 56% and 77% above control levels were achieved. Mean serum P concentrations were not decreased with low-dose cortisol phosphate infusion during the 12 days preceding menses, but mean serum P levels were decreased by 69% to 2.3 ng/mL during high-dose cortisol phosphate infusion. No corresponding decrease in excretion of conjugated immunoreactive P metabolites was found in daily urine samples during cortisol phosphate infusion, suggesting that production rates of P were unaltered by the cortisol phosphate treatment. Unbound serum cortisol increased by a mean of 162% above control levels during high-dose cortisol phosphate infusion, but no increase occurred in the percentage of unbound serum P. CONCLUSIONS: We conclude that elevation of serum cortisol in the range observed in chronically stressed individuals may severely decrease the available P to target organs by displacement of P from plasma proteins but does not inhibit ovarian steroidogenesis or ovulation.

Gonadotropin dynamics in women receiving immediate or delayed transdermal estradiol after oophorectomy.

A prospective study was performed in 24 premenopausal women to evaluate the gonadotropin dynamics of pharmacologic doses of transdermal estradiol-17 beta (E2) administered after bilateral oophorectomy. Patients were given 0.2-mg transdermal E2 patches for 2 weeks, followed by 0.1-mg patches for 4 weeks either immediately postoperatively (immediate estrogen replacement therapy [ERT]) or beginning 12-14 days after surgery (delayed ERT). Serum gonadotropins and E2 levels were measured serially, and postmenopausal symptoms were prospectively recorded. Administration of 0.2 mg transdermal E2 immediately after surgery suppressed the post-castration rise in gonadotropins for at least 4 days, but LH and FSH levels did increase to the menopausal range after 2 weeks despite continued therapy. Sustained circulating levels of E2 with transdermal E2 therapy were comparable to follicular phase values. Vasomotor symptoms were well controlled by 0.2 mg of transdermal E2 in the majority of patients during the clinical trial. There was no significant estrogen-related morbidity despite the large doses used. Two patients had skin irritation at the patch site causing discontinuation of therapy. These data suggest that large doses of transdermal E2 can suppress gonadotropin levels only for a brief interval. We were unable to demonstrate any long-term alteration in the hypothalamic-pituitary set point for sensitivity to exogenous E2.

Characteristics of the new progestogens in combination oral contraceptives.

This review details the characteristic features of three new progestogens which soon will be available in low-dose combination oral contraceptive agents in the United States. Available data suggest that desogestrel, gestodene, and norgestimate are extremely potent progestogens with few androgenic side effects. The smaller changes in lipids induced by these progestogens seem to confer some advantage to the use of preparations containing one of these agents. Whether this advantage is also present clinically remains to be determined.

PIP: 3 about-to-be marketed progestogens (desogestrel, gestodene, and norgestimate) are discussed in terms of their structural characteristics and metabolism, biological activity, effects on carbohydrate and lipid metabolism, and effects on coagulation. There appears to be little difference in clinical efficacy between the new progestogens and those currently available in the US. What difference, there is to be that the androgenic metabolic effects are minimized with the new progestogens. It is though that a comparison of the clinical benefits of these agents would be difficult. Synthetic progestogens are used in oral contraceptives (OC) in order to inhibit ovulation. In combination with estrogen, they can have antiestrogenic properties. Steroid dose and potency in OCs is noted as an important consideration in comparing progestogens. The new progestogens, like the US-marketed DL-norgestrel and levonorgestrel, are gonanes, which like estranes are structured with the absence of a methyl group between rings A and B and the presence of an ethinyl group in position 17 alpha. Each is different metabolically. Studies of the biological activity of these new progestogens are difficult to compare because of labeling, dose, experimental methods, measurement errors, and the inclusion of the estrogen component, which is known to be contributory to the side effects. Only potency can be compared and gestodene has the strongest effect on inhibiting ovulation an transforming the endometrium into secretory endometrium. All have little estrogenic effects an are weak antiestrogens, with little androgenic activity as measured by the increase in seminal vesicle or prostatic weight of laboratory animals. Circulatory bonding is found in various forms. Although not clinically demonstrated, it is possible that gestodene, which is a competitive inhibitor to aldosterone, may be useful to those with hypertension. Because of the marked increase in circulating concentrations of SHBG of gestodene and desogestrel, it may be useful to those with hirsutism upon additional clinical testing. The selected review of studies on the effects of the new progestogens on carbohydrate and lipid metabolism, including the HDL and LDL cholesterol levels, suggests small effects of questionable clinical significance. Based on clinical trials of gestodene in Europe, there appears to be no greater incidence of thromboembolic activity or effects on coagulation an fibrinolysis than previously reported.