Robert W. Rebar

The physiology and measurement of hot flushes

Hot flushes occur in the vast majority of women at menopause or after bilateral oophorectomy. Yet only in the last decade have the physiologic changes associated with hot flushes been identified. It is now clear that hot flushes occur together with pulsatile release of luteinizing hormone. Available data implicate the anterior hypothalamus in the pathogenesis of the hot flush and suggest involvement of catecholamines and endogenous opiates. Estrogen withdrawal appears to be the stimulus to the development of hot flushes in susceptible women, and likewise estrogen is the most effective agent in reducing the frequency and intensity of the hot flush.

Modulation of thymosin β4 by estrogen

Abstract The endocrine thymus produces several hormone-like peptides (generically termed thymosins) which control development of the thymic-dependent lymphoid system and participate in the process of immune regulation. In addition, recent literature supports the hypothesis that gonadal steroids in general and estrogens in particular affect the immune system. To determine whether steroid hormones modulate secretion of thymic peptides, basal concentrations of thymosins α 1 and β 4 were determined by radioimmunoassay in morning blood samples from 87 women in various clinical states. Basal concentrations of thymosin α 1 were similar in all women sampled. Basal levels of thymosin β 4 were similar in normal women during the early follicular phase, women with premature ovarian failure, postmenopausal women not receiving estrogen, and individuals with gonadal dysgenesis. However, the marked variability of basal levels in premature ovarian failure and in postmenopausal women suggests that these groups are quite heterogeneous. Thymosin β 4 concentrations were reduced in castrated women not receiving estrogen and were decreased more in both postmenopausal women and castrated women who were on chronic estrogen therapy. These data suggest that estrogens can modulate the circulating levels of thymosin β 4 but not of thymosin α 1 . We do not yet know whether sex steroids modulate secretion of other thymic peptides.

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.

The effects of thymus-derived peptides on hypothalamic LRF and pituitary gonadotropin content in prepubertal congenitally athymic nude mice and their normal heterozygous littermates.

Congenitally athymic nude mice have recognized reproductive defects, accompanied by decreased pituitary gonadotropin and hypothalamic LRF concentrations at 3 weeks of age, compared to their normal heterozygous littermates. To determine if these hormonal changes are due to decreased secretion of thymic peptides, we measured pituitary concentrations of LH and FSH and hypothalamic LRF content at 21 days of age in 122 congenitally athymic nude (nu/nu) mice and in 190 heterozygous (nu/+) littermates administered daily injections of a crude thymic extract, semipurified thymosin fraction 5, or a synthetic thymic protein preparation. All animals receiving crude thymic protein extract, and some receiving either thymosin or synthetic thymic factor, had reduced levels of hypothalamic LRF. The changes in concentrations of gonadotropins were more variable. All mice receiving crude thymic extract (with reduced hypothalamic LRF content) appeared to have increased pituitary concentrations of LH, FSH, or both when compared to control animals, although statistical significance was not achieved in all groups. A similar but less marked trend toward increased pituitary gonadotropins was also noted in mice receiving thymic factor. These preliminary results suggest that thymus-derived peptides can affect hypothalamic-pituitary function and support our hypothesis that thymic hormones may play a role in programming the hypothalamic-pituitary axis in the prepubertal period in rodents.

Insulin resistance and abnormal ovarian responses to human chorionic gonadotropin in chronically anovulatory women

We studied the interrelationships between insulin resistance, obesity, and abnormal ovarian androgen secretion in chronically anovulatory women with clinical or biochemical evidence of hyperandrogenism. Four groups of six subjects each were studied: (1) normal weight (within 10% ideal body weight) anovulatory, (2) obese (greater than 120% ideal body weight) anovulatory, (3) normal weight eumenorrheic, and (4) obese eumenorrheic. After dexamethasone suppression, human chorionic gonadotropin (2000 IU/1.5m2 body surface area intramuscularly) was administered to each subject. Serum testosterone levels were subsequently determined hourly for 17 hours. On a separate occasion, an oral glucose tolerance test was administered to five subjects from each group. Serum glucose and immunoreactive insulin levels were determined before and after the ingestion of a standard 100 gm glucose load. As a group, the anovulatory women had higher (p less than 0.05) basal testosterone levels (1005 +/- 97 pg/ml) than did the ovulatory women (241 +/- 21 pg/ml) (values +/- SE). Obesity per se was not associated with increased basal testosterone levels. Testosterone levels rose in response to human chorionic gonadotropin (p less than 0.005) only in obese anovulatory women, reached maximal levels after 3 hours, and subsequently remained stable. Basal immunoreactive insulin levels were elevated (p less than 0.05) only in obese anovulatory women (52.4 +/- 20 microU/ml) compared with obese eumenorrheic (8.7 +/- 1.0 microU/ml), normal weight anovulatory (5.8 +/- 2.4 microU/ml), and normal weight eumenorrheic (4.6 +/- 0.4 microU/ml) women. Similarly, maximal increases in immunoreactive insulin levels after glucose ingestion were significantly greater (p less than 0.01) in obese anovulatory women compared with other groups. Of note is the observation that maximal changes in testosterone observed within the first 3 hours after human chorionic gonadotropin and maximal changes in insulin were correlated (r = 0.91, p less than 0.01). These data suggest that (1) both insulin resistance and an abnormal acute response to human chorionic gonadotropin are seen only in obese anovulatory women and (2) the degree to which these two abnormalities are manifested is clearly correlated. The mechanism(s) responsible for this interrelationship, as well as the underlying cause(s) of these biochemical defects, remain to be elucidated.

Effects of Thymic Peptides on Hypothalamic-Pituitary Function

A role for the thymus gland within the immune system is now well recognized. Recent investigations have convincingly demonstrated that the thymus really functions as an endocrine organ, secreting peptides which influence lymphoid tissue structure and function (Goldstein et al., 1981). However, studies from our laboratory also suggest that thymic peptides may play a broader role within the endocrine system and may function as modulators of the hypothalamic-pituitary axis. In this brief review I shall attempt to delineate what we have learned about the apparent relationship between the thymus gland and other endocrine organs. I shall focus particularly on the effects of the thymus on the reproductive system but conclude by speculating about other possible functions for thymic peptides and suggest that the neuroendocrine and immune systems are tightly coupled and function together in a coordinated fashion.

Hypergonadotropic Forms of Amenorrhea

Circulating concentrations of follicle stimulating hormone (FSH) increase dramatically following both bilateral oophorectomy and the menopause. Thus, by definition, young women with hypergonadotropic amenorrhea should have premature ovarian failure (POF). This belief was based on the findings of Goldenberg et al. (1), who reported that without exception, individuals with FSH levels of greater than 40 mIU/mL 2nd IRP-hMG (International Reference Preparation-human menopausal gonadotropins) had no viable follicles on ovarian biopsy.