The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

PIP: 43 determinants of low birth weight were analyzed from 895 published papers in the English and French literature from 1970-1984 The assessment was limited to singleton births of women living at sea level with no chronic illness; rare factors and complications of pregnancy were excluded The 43 factors were categorized as genetic and constitutional, demographic and psychosocial, obstetric, nutritional, maternal morbidity during pregnancy, toxic exposure and antenatal care The existence and magnitude of a causal effect on birth weight, gestational age, prematurity and intrauterine growth retardation were determined by a set of methodological standards In developed countries, the most important factor was cigarette smoking, followed by nutrition and pre-pregnancy weight In developing countries the major determinants were racial origin, nutrition, low pre-pregnancy weight, short maternal stature, and malaria Pre-pregnancy weight, prior premature birth or miscarriage, diethylstilbestrol exposure and smoking were major determinants of gestational duration, but the majority of prematurity was unexplained in both developed and developing countries There is a need for future research on the effect of maternal work, prenatal care, and certain vitamin and mineral deficiencies on intrauterine growth, and the effect of genital tract infection, prenatal care, maternal employment, stress and anxiety on prematurity

Determinants of low birth weight: Methodological assessment and meta-analysis

I. Introduction IN THE adult ovary, folliculogenesis starts when follicles leave the pool of resting follicles (RF) to enter the growth phase. From there, the early growing follicle undergoes a developmental process including a dramatic course of cellular proliferation and differentiation. In primates, only one follicle commonly reaches the preovulatory stage every cycle; most follicles fail to complete this maturation scheme, dying in the process termed atresia. In recent years, a picture has emerged depicting the classic endocrine control of ovarian function by LH and FSH, entangled in a maze of regulatory systems hinging on cell-cell interactions between follicular cells, via action of a variety of molecules (1–3). Different types of cell-cell interactions have been described. In paracrine regulations, a molecule synthesized by one cellular type is released into the interstitial milieu to act directly on another cellular type. In autocrine regulations, molecules synthesized by one cellular type are rel...

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Regulation of ovarian follicular development in primates: facts and hypotheses.

Pregnancy has commonly been viewed as a cooperative interaction between a mother and her fetus. The effects of natural selection on genes expressed in fetuses, however, may be opposed by the effects of natural selection on genes expressed in mothers. In this sense, a genetic conflict can be said to exist between maternal and fetal genes. Fetal genes will be selected to increase the transfer of nutrients to their fetus, and maternal genes will be selected to limit transfers in excess of some maternal optimum. Thus a process of evolutionary escalation is predicted in which fetal actions are opposed by maternal countermeasures. The phenomenon of genomic imprinting means that a similar conflict exists within fetal cells between genes that are expressed when maternally derived, and genes that are expressed when paternally derived. During implantation, fetally derived cells (trophoblast) invade the maternal endometrium and remodel the endometrial spiral arteries into low-resistance vessels that are unable to constrict. This invasion has three consequences. First, the fetus gains direct access to its mother's arterial blood. Therefore, a mother cannot reduce the nutrient content of blood reaching the placenta without reducing the nutrient supply to her own tissues. Second, the volume of blood reaching the placenta becomes largely independent of control by the local maternal vasculature. Third, the placenta is able to release hormones and other substances directly into the maternal circulation. Placental hormones, including human chorionic gonadotropin (hCG) and human placental lactogen (hPL), are predicted to manipulate maternal physiology for fetal benefit. For example, hPL is proposed to act on maternal prolactin receptors to increase maternal resistance to insulin. If unopposed, the effect of hPL would be to maintain higher blood glucose levels for longer periods after meals. This action, however, is countered by increased maternal production of insulin. Gestational diabetes develops if the mother is unable to mount an adequate response to fetal manipulation. Similarly, fetal genes are predicted to enhance the flow of maternal blood through the placenta by increasing maternal blood pressure. Preeclampsia can be interpreted as an attempt by a poorly nourished fetus to increase its supply of nutrients by increasing the resistance of its mother's peripheral circulation.

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Genetic conflicts in human pregnancy.

The effects of sex and hormonal status on the physiological response to acute psychosocial stress.

The dynamics of ovarian and pituitary hormone changes during the midcycle period were evaluated. Changes in hormone levels were determined at 2-h intervals for 5 consecutive days during the periovulatory phase of the cycle in five women. During the 50 h preceding the onset of the surge, the rates of increments for estradiol (E2), progesterone (P4), and LH were similar, with doubling times of 57-61 h. The onset of LH and FSH surges was found to occur abruptly (LH doubled within 2 h). They were temporally associated with the attainment of peak E2 levels and occurred 12 h after the initiation of a rapid rise of P4. The mean duration of the surge was 48 h, with a rapidly ascending limb (doubling time, 5.2 h) lasting 14 h accompanied by a rapid decline of E2 and a continued rise of P4. The surge was followed by a peak plateau of gonadotropin levels lasting for 14 h and a transient leveling of P4. The longer descending limb (half-time, 9.6 h), lasting for 20 h, was associated with a second rapid rise of P4, beginning 36 h after surge onset or 12 h before termination of the surge. By using the onset of the LH surge as a reference point, our data provide a relatively precise picture of the hormonal changes preceding the onset of the gonadotropin surge and the temporal relationship between the multiphasic P4 rise and pituitary-ovarian function.

Hormonal Dynamics at Midcycle: A Reevaluation*

To determine whether endogenous opiates exert an inhibitory action on LH secretion during the menstrual cycle, LH increments were examined in response to a specific opiate antagonist, naloxone, infused at 1.6 mg/hr for 4 hrs. Naloxone had no discernible effect on LH release during the early follicular phase. By contrast, a significant LH increment was observed in both the late follicular and mid-luteal phases of the cycle but the patterns of LH increment were distinct. Late follicular subjects exhibited slow, progressive increases in LH, while prompt, episodic and quantitatively greater LH increments were evident in mid-luteal phase subjects. These observations suggest that endogenous opiates are involved in the regulation of LH secretion during the high estrogen and estrogen-progesterone phases of the menstrual cycle.

The role of endogenous opiates on lh secretion during the menstrual cycle

The effect of acute activation of the ACTH-adrenal axis on circulating testosterone (T) levels was investigated. Elevation of circulating cortisol resulting from insulin-induced hypoglycemia or the administration of hydrocortisone was followed by a rapid decrease in serum T levels, without accompanying changes in LH or PRL. These findings suggest that hypercortisolism of endogenous or exogenous sources suppresses T secretion by a direct action on the testis. This adrenal-testicular axis may have biological implications on the reproductive adaptation to stress.

Acute Suppression of Circulating Testosterone Levels by Cortisol in Men

To determine the basis of the reduced ovarian estrogen (E) production in polycystic ovary syndrome (PCO), the ability of granulosa cells from normal and polycystic ovaries to aromatize androgens was assessed both in vitro and in vivo. During a 5-h incubation in vitro with graded doses of aromatase substrate [androstenedione (Δ4), 10−10−10−6 M], a dose-related increase in E production was observed in granulosa cells from normal 8- to 15-mm follicles; the minimum and maximum effective doses of Δ4 were 10−10 and 10−7 M, respectively, and the ED50 was approximately 10−8 M. In contrast, granulosa cells from 4- to 6-mm follicles of both normal and polycystic ovaries produced negligible amounts of E when incubated 5 h with graded doses of Δ4,suggesting that the aromatase enzyme had not been induced in follicles of this size. To test the functional relationship between gonadotropins and E production in PCO and normal granulosa cells from the aromatase-deficient 4- to 6-mm follicles, these granulosa cells were cul...

Functional Studies of Aromatase Activity in Human Granulosa Cells from Normal and Polycystic Ovaries

To test the postulate that endogenous opioid peptides may be involved in the neuroendocrine mechanisms controlling the frequency and amplitude of LH pulses, saline and an opioid receptor antagonist, naloxone, were infused sequentially, each for 6-h intervals, in six normal cyclingwomen during the luteal phase of the menstrual cycle. During naloxone infusion (1.6 mg/h), there was a significant (P <0.01) increase in both the frequency and amplitude of LH pulses compared tothose in saline controls. FSH pulses were not discernible in individual subjects; however, a significant increment in FSH levels occurred concomitantly with the increase in LH. These data strongly suggest that endogenous opiates, through an inhibition of hy-pothalamic LRF, participate in the endocrine events leading to the low frequency of episodic LH secretioncharacteristic of the luteal phase of the human menstrual cycle.

M. E. Quigley

Papers

Hormonal Dynamics at Midcycle: A Reevaluation*

The role of endogenous opiates on lh secretion during the menstrual cycle

Acute Suppression of Circulating Testosterone Levels by Cortisol in Men

Functional Studies of Aromatase Activity in Human Granulosa Cells from Normal and Polycystic Ovaries

Endogenous opiates modulate pulsatile luteinizing hormone release in humans.