Postmenopausal estrogen therapy and cardiovascular disease.
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Coronary Disease↗
Biomedical subjects
J C Prior
Publications and source records attributed to J C Prior.
Reproduction for the athletic woman. New understandings of physiology and management.
A physically active and athletic lifestyle is not only a healthy but a fulfilling choice for women. Although there is extensive literature on 'athletic amenorrhoea' which implies that exercise causes loss of the menstrual cycle, there is inadequate scientific evidence for a causal relationship. The reproductive system adapts to environmental, nutritional, emotional and physical stressors or 'threats' by downward adjustment towards the premenarcheal pattern. The hormonal milieu of this adaptation is low gonadal steroid and high glucocorticoid levels which synergistically increase the risk for a negative bone balance. Athletic women may become amenorrhoeic if reproductive immaturity, emotional stress and undernutrition coexist with increasing exercise loads. Treatment for athletic women with menstrual cycle changes requires that hypothalamic stressors be identified and decreased. In addition, as progesterone deficiency (from disorders of ovulation, whether flow is regular or absent) is the most prevalent menstrual cycle change, treatment with medroxyprogesterone on days 16 to 25 of their cycle will not only provide regular flow (if estrogen levels are sufficient) but will also promote increased bone density.
Adaptation, Physiological↗
Ovulation disturbances and exercise training.
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Anovulation↗
Spinal bone loss and ovulatory disturbances.
BACKGROUND: Osteoporosis develops in women with estrogen deficiency and amenorrhea who lose bone at an accelerated rate. It is not known to what extent bone loss differs between ovulatory women with regular menstrual cycles who are training intensely and those who are sedentary. METHODS: We measured the density of cancellous spinal bone from the 12th thoracic vertebra to the 3rd lumbar vertebra by quantitative computed tomography on two occasions one year apart in 66 premenopausal women 21 to 42 years of age. All the women had two consecutive ovulatory cycles immediately before entering the study. Twenty-one women were training for a marathon, 22 ran regularly but less intensively, and 23 had normal levels of activity. The lengths of the women's menstrual cycles and luteal phases, diet, exercise levels, and hormonal levels were also determined. We defined ovulatory disturbances as anovulatory cycles and cycles with short luteal phases. RESULTS: The mean (+/- SD) spinal bone density in the 66 women decreased 3.0 +/- 4.8 mg per cubic centimeter per year (2.0 percent per year) (P less than 0.001). Amenorrhea did not develop in any woman during the year of observation (only 2.7 percent of the cycles were greater than 36 days long). Ovulatory disturbances occurred in 29 percent of all cycles, however. Bone loss was strongly associated with these disturbances (r = 0.54, 24 percent of the variance). The 13 women who had anovulatory cycles lost bone mineral at a rate of 6.4 +/- 3.8 mg per cubic centimeter per year (4.2 percent per year). The women training for a marathon had menstrual cycles similar to those of the women in the other two groups. CONCLUSION: Decreases in spinal bone density among women with differing exercise habits correlated with asymptomatic disturbances of ovulation (without amenorrhea) and not with physical activity.
Adult↗
Progesterone as a bone-trophic hormone.
Experimental, epidemiological, and clinical data indicate that progesterone is active in bone metabolism. Progesterone appears to act directly on bone by engaging an osteoblast receptor or indirectly through competition for a glucocorticoid osteoblast receptor. Progesterone seems to promote bone formation and/or increase bone turnover. It is possible, through estrogen-stimulated increased progesterone binding to the osteoblast receptor, that progesterone plays a role in the coupling of bone resorption with bone formation. A model of the interdependent actions of progesterone and estrogen on appropriately-"ready" cells in each bone multicellular unit can be tied into the integrated secretions of these hormones within the ovulatory cycle. Figure 5 is an illustration of this concept. It shows the phases of the bone remodeling cycle in parallel with temporal changes in gonadal steroids across a stylized ovulatory cycle. Increasing estrogen production before ovulation may reverse the resorption occurring in a "sensitive" bone multicellular unit while gonadal steroid levels are low at the time of menstrual flow. The bone remodeling unit would then be ready to begin a phase of formation as progesterone levels peaked in the midluteal phase. From this perspective, the normal ovulatory cycle looks like a natural bone-activating, coherence cycle. Critical analysis of the reviewed data indicate that progesterone meets the necessary criteria to play a causal role in mineral metabolism. This review provides the preliminary basis for further molecular, genetic, experimental, and clinical investigation of the role(s) of progesterone in bone remodeling. Much further data are needed about the interrelationships between gonadal steroids and the "life cycle" of bone. Feldman et al., however, may have been prophetic when he commented; "If this anti-glucocorticoid effect of progesterone also holds true in bone, then postmenopausal osteoporosis may be, in part, a progesterone deficiency disease."
Animals↗
Determination of luteal phase length by quantitative basal temperature methods: validation against the midcycle LH peak.
Basal temperature data are known to provide unreliable assessments of luteal phase length when they are evaluated by qualitative, visual-pattern methods. This study of 24 cycles in 24 women compared the serum LH peak day with the luteal phase onset day determined by three quantitative basal temperature methods: a) a new computerized least mean square method developed by the authors; b) the mean temperature method reported by Vollman; and c) a computerized version of the World Health Organization cumulative sum method of Royston. The luteal phase onset day determined by the three quantitative basal temperature methods, (a, b, and c) correlated well with the midcycle LH peak (r = 0.879, 0.891, and 0.791, respectively, all p less than 0.001). The cumulative sum method, however, was only able to analyze 19/24 cycles. The mean delay between the LH peak day and the luteal phase onset day determined by thermal shift was 2.4 +/- 1.5, 2.7 +/- 1.4, and 4.1 +/- 2.0 d (mean +/- SD), respectively. The mean temperature method, but not the other two methods, showed an increasing delay between the LH peak day and the thermal shift day with longer follicular phase lengths. Rectal and oral temperature data from the same cycle give identical luteal onset days when analyzed by the least mean square and mean temperature methods, but discrepant days by the cumulative sum analysis. The least mean square technique is a reliable and precise method for population documentation of luteal phase lengths.
Adult↗
Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism.
The clinical and hormonal response to 12-month therapy with the antiandrogen, spironolactone, in conjunction with near-physiologic doses of female gonadal steroids in 50 transsexual males, is presented. An unselected referred series of 61 men with the psychiatric diagnosis of transsexualism was treated; 10 subjects who had received previous gonadal surgery and 1 man with Klinefelter's syndrome were excluded. Twenty-seven conventionally treated (CT; high-dose estrogen), age 34.4 +/- 10.5 years, mean +/- SD, and 23 untreated patients (SPS), age 30.7 +/- 6.2 years, were studied. Following the initial visit, all 50 were begun on spironolactone and low-dose female hormone therapy. Despite high-dose estrogen treatment for more than 2 years, the mean testosterone (T) level for the CT group was not in the female range (169 +/- 193 ng/dl; normal 20-80). Spironolactone, in doses of 200-600 mg/day, lowered T to the female range in both groups after 12 months (CT 87 +/- 111 and SPS 49 +/- 41 ng/dl). This was achieved in the CT group despite decreases in estrogen dose and discontinuation of parenteral therapy. SPS subjects experienced significant decreases in plasma T (642 +/- 236 to 49 +/- 41 ng/dl, p less than 0.001). Systolic blood pressure dropped (128 +/- 14 to 121 +/- 14 mm Hg, p less than 0.05). The clinical response, including decreased male pattern hair, breast development, feminization, and lack of erections was excellent in most subjects.
Adult↗
Acute arsenic toxicity--an opaque poison.
We report a patient with fatal acute arsenic poisoning presenting as vomiting and diarrhea with the finding of intra-abdominal radiopacities on radiographs. These represent the classic features of acute arsenic toxicity and are detailed here as a reminder to others facing a similar puzzling patient with this potentially treatable poisoning.
Abdomen↗
Physicochemical characterization and functional activity of fibroid prolactin produced in cell culture.
Evidence from our laboratory with the use of cultured (primary and passaged) cells has extended our initial observation that human uterine fibroid is an extrapituitary source of prolactin. Fibroid prolactin antigen in conditioned medium reacted specifically in radioimmunoassay for human pituitary prolactin. Control experiments demonstrated that the radioimmunoassay results were not spurious due to degradation of tracer 125I-labeled prolactin. Immunoparallel dilution curves indicated antigenic relatedness of pituitary and fibroid prolactin. In a calibrated Sephadex G-100 column, fibroid prolactin eluted in the same region (20.3 to 20.9 kd) as purified pituitary prolactin. Glycosylated prolactin, detected by concanavalin A affinity column chromatography, appeared to constitute only a small percentage of fibroid prolactin made in culture. The ratio of fibroid prolactin bioactivity (lactogen Nb2 lymphoma bioassay) to antigen (radioimmunoassay) was 0.77. These data indicate that human uterine fibroid tissue produces a molecule similar to or, perhaps, identical with pituitary prolactin.
Cells, Cultured↗
Reversible reproductive dysfunction in men with obstructive sleep apnoea.
A central, reversible decrease in male sexual function appears related to some aspect of obstructive sleep apnoea (OSA). Lower serum testosterone (T) levels were documented in 15 men with OSA versus nine snorers (no OSA), (9.18 +/- 0.92 vs 11.55 +/- 0.90 nmol/l, mean +/- SEM), P less than 0.05 in a consecutive case series of 24 men referred for diagnostic overnight sleep studies. Gonadotrophins did not differ between the two groups. Although the men with OSA did not differ in body mass index (BMI) or weight from the snorers, they were older (51 +/- 3.9 vs 44 +/- 3.1 years), P less than 0.02. Serum T did not correlate with age, but was correlated with minimum nocturnal arterial oxygen saturation (Min SaO2) (r = 0.589), P less than 0.02. A prospective controlled trial of uvulopalatopharyngoplasty therapy (UPP) for OSA in 12 subsequent subjects showed reproductive improvement which was parallel with improved apnoea at 3 months postsurgery. T increased (13.31 +/- 1.07 to 16.59 +/- 0.72 nmol/l), P less than 0.02, without significant changes in BMI, serum PRL, LH or FSH. All seven of the men who reported decreased sexual interest prior to surgery felt their libido and sexual functioning had returned to normal 3 months following UPP. Some aspect of OSA in men appears to produce a reversible hypothalamic-pituitary reproductive dysfunction.
Adult↗
Conditioning exercise decreases premenstrual symptoms: a prospective, controlled 6-month trial.
Six months of exercise training was associated with decreased premenstrual symptoms in two groups of women. There was no change in symptoms in nontraining women. Eight sedentary (ST) women increased running from 0 to 76 +/- 26 km/cycle (mean +/- standard deviation) over 6 months and seven runners (MT) trained for a marathon (42.2 km). Six normally active, nontraining (C-NT) women kept their activity constant. Each subject completed monthly intensity-graded questionnaires or kept daily symptoms diaries concerning premenstrual symptoms. All monitored basal body temperature, weight, and exercise. Gonadal steroids were measured in ST women. For ST subjects, breast (P = 0.005), fluid (P = 0.01), and personal stress (P = 0.025) decreased. MT women experienced decreased fluid (P = 0.034) and depression (P = 0.014). Anxiety tended to decrease (P = 0.087). ST and MT subjects experienced decreases in premenstrual symptoms without documented hormonal, menstrual cycle, or weight changes. These symptom changes appear to be the earliest evidence of the effects of conditioning exercise on the reproductive system.
Adult↗
Physical exercise and the neuroendocrine control of reproduction.
Reproductive change during conditioning exercise (physical training provides a model of hypothalamic adaptation to alterations in the external and internal environment. Parallels exist between the reproductive changes with exercise and those occurring with physical illness, undernutrition and psychological trauma. Although menstrual cyclicity may be disrupted in younger women, luteal phase shortening, anovulation and decreased premenstrual symptoms within normal ovulatory cycles are the most frequent observations noted. Baseline LH, prolactin and oestradiol tend to be lower, and other hormones unchanged, in trained women. Testosterone may be decreased within the normal range in men. Recent evidence shows that LH pulse frequency, amplitude and area under the LH curve are decreased in both female and male runners. Interrelationships between increases in central dopamine, endorphin and probably some hypothalamic message(s) relating to nutritional state appear to modulate these reproductive changes. The clinical and therapeutic response to reproductive alterations in the context of exercise differs when these are seen as adaptive and not as disease processes (Prior and Vigna, 1985b).
Energy Metabolism↗
Testosterone-related exacerbation of a prolactin-producing macroadenoma: possible role for estrogen.
Men with PRL-producing macroadenomas often present with hypogonadism and impotence. This report documents exacerbation of a PRL-secreting tumor after two separate 200-mg testosterone enanthate (T) injections despite continued bromocriptine (BRC) therapy. A 37-yr-old man with a 60-mm invasive tumor and a serum PRL level of 13,969 +/- 332 ng/ml (mean +/- SD) responded to BRC therapy with rapid disappearance of visual field defect, headache, and facial pain as well as decrease in serum PRL to 5,103 +/- 1,446 ng/ml. T injection was followed by severe headache, facial pain, and increase in PRL to 13,471 ng/ml. Visual field deterioration and increased tumor size (height, 40-43 mm) by computed tomography were documented. A relationship between T injection and exacerbation of the prolactinoma was not recognized until after a second T injection 3 months later. After that therapy, baseline PRL increased from 6,900 to 12,995 ng/ml. The hypothesis that T was aromatized to estradiol, directly stimulating lactotrophs, was supported by an increase in serum estradiol from 24 to 51 pg/ml after the second T injection. Although T treatment is accepted as appropriate therapy for hypogonadism in men with prolactinomas, it may not only interfere with the response of the tumor to BRC therapy, but even stimulate tumor growth and secretion.
Adenoma↗
Conditioning exercise and premenstrual symptoms.
Exercise is commonly listed as a remedy for the premenstrual syndrome (PMS), although no study has proven that it is an effective therapy. Numerous reports have suggested that exercise is associated with improved mood and symptoms. In those reports, however, the diagnosis of PMS was not clearly documented, nor was the exercise carefully controlled. Preliminary evidence suggests that exercise training in ovulatory, sedentary women and intensified training in women athletes decrease mild premenstrual symptoms. Although conditioning exercise is associated with short luteal phase and anovulatory cycles, decreases in mild premenstrual symptoms occur prior to menstrual cycle changes. Controlled studies of PMS and exercise training may not only document an effective, nonpharmacologic therapy for PMS but also clarify the hormonal etiology of this complex biobehavioral phenomenon.
Adult↗
Conditioning exercise decreases premenstrual symptoms. A prospective controlled three month trial.
Conditioning exercise decreased premenstrual symptoms during 3 months of a prospective controlled training study. Eight women with normal ovulatory menstrual cycles began a running exercise training programme while completing intensity-graded questionnaires concerning molimina. Six sedentary control women followed the same protocol for 3 months but did not exercise. Oral basal temperatures evaluated by mean temperature analysis were obtained for all cycles. Exercise distance and time, average exercise heart rate, basal and maximal heart rate and body weights were recorded prospectively and evaluated during the control (0) and 3rd month of the study. Mid-luteal phase progesterone and estrogen levels were sampled during the analyzed cycles for the exercise group. Molimina did not change over 3 months time in the control group. The exercise group, after increasing distance run to 51.0 +/- 18.1 km/cycle at 3 months, showed decreases in overall molimina (scores on a 9-point scale) 6.5 +/- 1.8 to 3.5 +/- 0.9, p less than 0.01). Breast symptoms decreased from 8.3 +/- 0.7, p less than 0.005. Fluid symptoms also decreased from 7.3 +/- 1.8 to 5.5 +/- 0.9, p less than 0.025. Menstrual cycle intervals, luteal lengths, body weights and mid-luteal estrogen and progesterone levels were normal and unchanged. Moderate exercise training without major weight, hormonal or menstrual cycle alteration significantly decreased premenstrual symptoms.
Adult↗
Gonadotrophin-secreting pituitary tumour: report and review.
A 34-year-old male with a pituitary adenoma was investigated and demonstrated to have hypersecretion of both gonadotrophins in the basal state. Immunocytochemical staining and electron microscopic examination were positive for tumour cells secreting FSH and LH. Presenting symptoms included visual disturbances, loss of libido, impotence, cold intolerance, frontal headaches, change in skin pigmentation and excessive weight gain. The patient denied alteration in hair distribution, had no acral features, galactorrhoea or gynaecomastia. Surgical extirpation resulted in complete amelioration of his symptoms over a three year follow-up period. Basal and stimulated pituitary function testing results returned to normal post-operatively. A review of the literature documents six other cases of pituitary tumour secreting both LH and FSH in the basal state. More commonly, the pituitary adenoma secretes FSH only. The literature is reviewed with regard to both types of tumour.
Adenoma↗
Bioactive forms of serum lactogens: effects of treatment of prolactinoma patients with bromocriptine.
An in vitro bioassay for lactogenic hormones, based on the specific mitogenic effects of lactogens on cultured Nb2 node rat lymphoma cells, was used to measure the levels of lactogens in whole serum and in fractionated serum samples from three patients with prolactin (PRL) secreting pituitary adenomas. Under basal conditions, after pituitary stimulation, and following treatment with bromocriptine which greatly decreased the serum PRL levels, the bioassay (BA) results closely paralleled fluctuations in the sum of radioimmunoassay (RIA) estimates of serum PRL and growth hormone concentrations. The extreme sensitivity (10 pg/ml) of the BA facilitated measurement of PRL in fractions obtained after Sephadex G-100 chromatography of only 0.1 to 0.3 ml of sera from both untreated and bromocriptine-treated prolactinoma patients. In both types of samples, similar heterogenous patterns of bioactive PRL were observed, although most of the recovered activity appeared to be due to monomeric PRL. BA and RIA of fractions obtained after DEAE cellulose chromatography of sera from untreated prolactinoma patients revealed two PRL peaks, the first one containing 75% of the activity. Therapy with bromocriptine led to a reduction in the total serum PRL activity and, in particular, in the activity of the second peak.
Adenoma↗
Prolactin production from proliferative phase leiomyoma.
In vivo and in vitro endometrial stromal synthesis of prolactin occurs after progesterone-induced decidualization. Synthesis of prolactin by myometrium in vitro suggests that cells whose embryologic origin is the loose mesenchyme surrounding the paramesonephric ducts may retain the capacity to synthesize prolactin. Since physiologic myometrial synthesis of prolactin has not been demonstrated in vivo, prolactin genome expression in pathologic conditions was considered. Follicular phase leiomyomas were diced to 8 mm3 and cultured in Dulbecco's modified Eagle's medium (DMEM) with either no hormones, estradiol 200 pg/ml, progesterone 20 ng/ml, or estradiol and progesterone. Media were sampled and changed every other day for 8 days, followed by culture in tritium-labeled leucine DMEM for 2 days. Portions of leiomyomas were homogenized for initial prolactin content, and all samples were assayed for prolactin by radioimmunoassay. Follicular phase leiomyomas contained prolactin (47 +/- 15 ng/gm) in excess of normal serum values. Synthesis was demonstrated during all time periods from leiomyomas not exposed to progesterone. Progesterone variably suppressed the synthesis of prolactin until after 144 hours of culture. Determination of molecular weight on a 60 by 1.5 cm Sephadex G-100 column revealed identical estimates for pituitary, decidual, and leiomyoma prolactin. Tritium-labeled leucine incorporation into prolactin was confirmed by immunoprecipitation of Sephadex G-100 column fractions. Similar antigenicity was confirmed by parallel dilution curves for pituitary, decidual, and leiomyoma prolactin. Preliminary bioactivity in lymphoma proliferation assays confirmed prolactin activity. The conclusion reached was that proliferative phase leiomyomas contained elevated prolactin presumably secondary to in vivo synthesis. This synthesis was confirmed in vitro.
Culture Techniques↗