Dean A. Van Vugt

Weight-related changes in reproductive function

Both low body weight and obesity can effect menstrual function and fertility. Although body weight is a significant factor current research suggests that a combination of physical psychological and nutritional stresses act additively in the determination of the onset and rate of pubertal progression menstruation and fertility. Abrupt or marked weight loss particularly when combined with physical or psychological stress has been shown to disrupt hypothalamic gonadotropin-releasing hormone leading at 1st to subtle endocrine abnormalities such as luteal phase defects and ultimately to oligomenorrhea or amenorrhea. The degree of hypothalamic dysfunction is in part linked to the percentage of body fat rather than body weight. In cases of obesity there appear to be complex pathophysiologic mechanisms involving changes in sex hormone binding globulin altered ovarian and adrenal androgen production changes in peripheral aromatization of androgens to estrogen and inappropriate gonadotropin secretion. Obese anovulatory women show higher concentrations of estrone and E2 than ovulatory obese women or women of normal weight. In most cases the process of weight reduction is sufficient to initiate resumption of menstrual cyclicity.

Effect of menstrual cycle phase on corticolimbic brain activation by visual food cues

Food intake is decreased during the late follicular phase and increased in the luteal phase of the menstrual cycle. While a changing ovarian steroid milieu is believed to be responsible for this behavior, the specific mechanisms involved are poorly understood. Brain activity in response to visual food stimuli was compared during the estrogen dominant peri-ovulatory phase and the progesterone dominant luteal phase of the menstrual cycle. Twelve women underwent functional magnetic resonance imaging during the peri-ovulatory and luteal phases of the menstrual cycle in a counterbalanced fashion. Whole brain T2* images were collected while subjects viewed pictures of high calorie (HC) foods, low calorie (LC) foods, and control (C) pictures presented in a block design. Blood oxygen level dependent (BOLD) signal in the late follicular phase and luteal phase was determined for the contrasts HC-C, LC-C, HC-LC, and LC-HC. Both HC and LC stimuli activated numerous corticolimbic brain regions in the follicular phase, whereas only HC stimuli were effective in the luteal phase. Activation of the nucleus accumbens (NAc), amygdala, and hippocampus in response to the HC-C contrast and the hippocampus in response to the LC-C contrast was significantly increased in the late follicular phase compared to the luteal phase. Activation of the orbitofrontal cortex and mid cingulum in response to the HC-LC contrast was greater during the luteal phase. These results demonstrate for the first time that brain responses to visual food cues are influenced by menstrual cycle phase. We postulate that ovarian steroid modulation of the corticolimbic brain contributes to changes in ingestive behavior during the menstrual cycle.

A randomized, placebo-controlled, crossover trial of danazol for the treatment of premenstrual syndrome.

To investigate whether danazol is more effective than placebo for the treatment of premenstrual syndrome (PMS), we conducted a randomized, double-blind, crossover study comparing three successive cycles of danazol (200 mg bid) to three cycles of placebo. Thirty-one women meeting rigorous criteria for a diagnosis of severe PMS over two pretreatment cycles were enrolled; 28 of these subjects completed at least one cycle of treatment with symptom recordings, which were entered into the analysis. A significant period effect confounded the planned within-subject analysis and therefore, the main treatment comparisons were confined to the first period only. Symptom scores on the Premenstrual Tension Self-Rating Scale (PMTS), Beck Depression Inventory (BDI), and a Visual Analogue Scale (VAS) were compared for the premenstrual week in the last cycle of treatment. For the 16 patients on danazol, scores on the PMTS decreased by an average of 14.0 (10.7) (standard deviation) points from a baseline of 25.4 (5.6) points. For the 12 patients on placebo, PMTS scores decreased by an average of 3.6 (9.5) points from a baseline of 23.5 (5.8) points (14.0 vs. 3.6; p = .0133, unpaired t-test). Seven (43.8%) of the subjects on danazol achieved a clinically relevant reduction of symptoms into the asymptomatic range (PMTS scores < or = 5) as compared to one (8.3%) of the subjects on placebo. Thus, danazol (200 mg bid) provided greater relief from severe PMS during the premenstrual week than did placebo.

Brain imaging studies of appetite in the context of obesity and the menstrual cycle

BACKGROUND Obesity affects many aspects of health, including reproduction. Despite unrelenting warnings about the health consequences of obesity, its prevalence continues to rise. Beginning with the discovery of leptin in 1994, the endocrinology of energy homeostasis has been significantly advanced. More recently, brain imaging studies have been providing novel insights into homeostatic and hedonic aspects of human ingestive behavior. METHODS A comprehensive MEDLINE search was conducted on the topic of neuroendocrine control of ingestive behavior with an emphasis on functional magnetic resonance imaging studies. Additional articles were collected by hand searching the bibliographies of all relevant articles retrieved. RESULTS This review describes recent advances in our understanding of endocrine signals that respond to acute and chronic energy states and regulate ingestive behavior so as to achieve a balance between energy intake and energy expenditure. Recently published brain imaging studies, describing the neural networks that process endocrine signals of energy state and hedonic cues associated with highly palatable foods, are highlighted. Brain responses to food cues are described in the context of appetite changes during the menstrual cycle both in normal physiology and under the conditions anorexia nervosa and bulimia nervosa. CONCLUSIONS The prevalence of obesity belies the plethora of endocrine signals in place to ensure energy homeostasis. However, satiety signals appear to be counteracted by hedonic signals derived from highly palatable foods typical of todays diet. A better understanding of the interaction between homeostatic and hedonic signals is needed to devise effective strategies for dealing with obesity. Menstrual cycle dependent changes in brain responses to food cues may provide insight into the normal physiological control of ingestive behavior as well as dysfunctional regulation associated with disordered eating.

Evidence of lasting functional destruction of the rat en dometrium after 5-aminolevulinic acid—induced photodynamic ablation: Prevention of implantation

OBJECTIVE We evaluated disruption of endometrial function after treatment with 5-aminolevulinic acid with or without light exposure. STUDY DESIGN In a conventional laboratory setting adult Sprague-Dawley female rats were treated with various doses of 5-aminolevulinic acid in one uterine horn and saline in the contralateral horn. Three hours after treatment both uterine horns were exposed to light, and the rats were bred to a fertile male 10 or 60 days later. Ablation of endometrium was evaluated by both rate of implantation and histologic features. RESULTS In the absence of light exposure 5-aminolevulinic acid had no significant effect on the rate of implantation, compared with saline (76% vs 92%, n = 25, p > 0.05). In contrast, 5-aminolevulinic acid treatment plus light exposure profoundly decreased the rate of implantation in the 5-aminolevulinic acid-treated uterine horns of rats bred 10 days (3.8% vs 100%, n = 26, p < 0.001) or 60 days after treatment (16.7% vs 100%, n = 24, p < 0.001). Histologic examination revealed that the 5-aminolevulinic acid plus light-treated uterine horns were completely devoid of endometrium. CONCLUSION Photodynamic treatment with 5-aminolevulinic acid resulted in a persistent disruption of rat endometrial function and was consistent with the histologic evidence of complete endometrial ablation. In addition, a partial destruction of myometrium adjacent to endometrium was observed. The myometrial damage may be through a nonphotodynamic mechanism because myometrium is unable to synthesize protoporphyrin IX from 5-aminolevulinic acid.

Vasopressin Mediates Hypoglycemia-Induced Inhibition of Luteinizing Hormone Secretion in the Ovariectomized Rhesus Monkey

The objective of the present study was to examine the role of vasopressin in the regulation of LH secretion in the rhesus monkey. The effect of vasopressin administration on basal LH secretion and vasopressin antagonism on stress-induced inhibition of LH secretion were examined. Intracerebroventricular (i.c.v.) infusion of vasopressin (20 micrograms/h) to chair restrained ovariectomized rhesus monkeys (n = 5) decreased the area under the LH curve by -51.61 +/- 13.73 ng/ml/h compared to -8.35 +/- 7.11 ng/ml/h following infusion of artificial CSF (aCSF; p = 0.021). This effect was independent of any change in mean arterial pressure. Subsequently, the role of vasopressin in hypoglycemia-induced suppression of LH was examined. Administration of insulin (1 U/kg BW) to chair-restrained ovariectomized rhesus monkeys decreased the area under the LH curve by -60.88 +/- 19.77 ng/ml/h. The decrease in LH was significantly different from that observed in aCSF-infused euglycemic controls which exhibited a slight decrease in LH (-8.35 +/- 7.11 ng/ml/h; p = 0.036). In contrast, the area under the LH curve was increased slightly (1.42 +/- 11.93 ng/ml/h) when insulin administration was combined with i.c.v. infusion of the vasopressin antagonist [deaminopenicillamine1, O-methyl-tyrosine2, arginine8]-vasopressin (120 micrograms/h; p = 0.013 vs. insulin only). The demonstration that vasopressin administration inhibits LH secretion whereas vasopressin antagonism prevents hypoglycemia-induced LH suppression suggests that vasopressin is a physiological inhibitor of LH secretion in the rhesus monkey.

Incidence and complications of multiple gestation in Canada: proceedings of an expert meeting

This paper reports the proceedings of a consensus meeting on the incidence and complications of multiple gestation in Canada. In addition to background presentations about current and possible future practice in Canada, the expert panel also developed a set of consensus points. The need for infertility to be understood, and funded, as a healthcare problem was emphasized, along with recognition of the emotional impact of infertility. It was agreed that the goal of assisted reproduction treatment is the delivery of a single healthy infant and that even though many positive outcomes have resulted from twin or even triplet pregnancies, the potential risks associated with multiple pregnancy require that every effort be made to achieve this goal. The evidence shows that treatments other than IVF (such as superovulation and clomiphene citrate) contribute significantly to the incidence of multiple pregnancy. There is an urgent need for studies to understand better the usage and application of these other fertility technologies within Canada, as well as the non-financial barriers to treatment. The final consensus of the expert panel was that with adequate funding and good access to treatment, it will be possible to achieve the goal of reducing IVF-related multiple pregnancy rates in Canada by 50%.

Hypoglycemia-lnduced Inhibition of LH and Stimulation of ACTH Secretion in the Rhesus Monkey is Blocked by Alprazolam

Insulin-induced hypoglycemia inhibits luteinizing hormone (LH) secretion and has been used as a model to study stress-induced inhibition of reproductive function. Endogenous opioid peptides have been implicated in mediating the inhibitory effect of hypoglycemia on LH secretion in sheep and rat. The objective of the present study was to determine if corticotropin-releasing hormone (CRH) and endogenous opiates are involved in the LH response to hypoglycemia in the nonhuman primate. Blood samples were collected at 15-min intervals for 6 h from ovariectomized rhesus monkeys (n = 6). Hypoglycemia was induced by injecting insulin 1 h after initiating blood collection. Animals were pretreated 15 min prior to insulin with either saline (n = 6), naloxone, a nonselective opiate receptor antagonist (n = 4), or alprazolam (n = 6), a potent benzodiazepine which has been shown to inhibit CRH. The LH, glucose, adrenocorticotropin (ACTH), and cortisol responses to insulin were determined. Insulin-induced hypoglycemia significantly inhibited LH secretion and increased ACTH and cortisol concentrations. Alprazolam prevented hypoglycemia-induced inhibition of LH independent of an effect on glucose concentrations. The mean (+/- SEM) LH pulse interval in response to hypoglycemia was decreased in the alprazolam pretreated group compared to the saline pretreated group (77.4 +/- 6.0 vs. 130.0 +/- 18.4 min), while LH pulse amplitude and mean LH levels were significantly increased (56.2 +/- 7.1 vs. 28.3 +/- 5.5 ng/ml, and 105.6 +/- 14.4 vs. 60.9 +/- 12.1 ng/ml respectively). In contrast, naloxone did not prevent hypoglycemia-induced LH inhibition. The mean LH pulse interval, LH pulse amplitude, and LH concentration in the naloxone pretreated monkeys were 152.1 +/- 33.4 min, 37.1 +/- 8.9 ng/ml, and 63.7 +/- 9.1 ng/ml respectively. Alprazolam pretreatment also markedly attenuated the ACTH response to hypoglycemia whereas the cortisol response was only moderately affected. We conclude that insulin-induced hypoglycemia in the monkey inhibits LH secretion through a mechanism involving CRH but not endogenous opiates.

Effect of Fasting on Cocaine-Amphetamine-Regulated Transcript, Neuropeptide Y, and Leptin Receptor Expression in the Non-Human Primate Hypothalamus

Leptin is a cytokine produced by white adipose tissue that circulates in direct proportion to adiposity and is an important signal of energy balance. Leptin inhibits food intake in rodents by inhibiting the orexigenic neuropetides neuropeptide Y (NPY) and agouti regulated peptide (AgRP) and stimulating the anorexigenic neuropeptides α-melanocyte-stimulating hormone (α-MSH) and cocaine-amphetamine-regulated transcript (CART). In order to extend our understanding of neuroendocrine regulation of appetite in the primate, we determined the effect of a metabolic challenge on CART, NPY, and leptin receptor (Ob-R) messenger ribonucleic acid (mRNA) in the nonhuman primate (NHP) hypothalamus. Ten adult female rhesus monkeys were either maintained on a regular diet or fasted for two days before euthanasia. CART, NPY, and Ob-R mRNA were measured by in situ hybridization histochemistry (ISHH). A 2-day fast decreased CART expression in the ARC, increased NPY gene expression in the supraoptic nucleus (SON) and paraventricular nucleus (PVN), and increased Ob-R expression in the ventromedial nucleus (VMN). This is the first report that fasting inhibits CART expression and stimulates Ob-R expression in monkeys. Increased NPY expression in the SON and PVN, but not the ARC of fasted monkeys also is novel. With some exceptions, our observations are confirmatory of findings in rodent studies. Similarities in the neuroendocrine responses to a metabolic challenge in monkeys and rodents support extending existing hypotheses of neuroendocrine control of energy homeostasis to primates.

Fluorescence and photosensitization of experimental endometriosis in the rat after systemic 5-aminolevulinic acid administration: A potential new approach to the diagnosis and treatment of endometriosis

OBJECTIVE Our purpose was to evaluate and compare the conversion of 5-aminolevulinic acid into the endogenous photosensitizer protoporphyrin IX in experimentally induced endometriosis and in other normal tissues in a rat model. STUDY DESIGN Fluorescence of experimental endometriotic lesions, uterus, peritoneum, bowel mesentery, bladder, eye, skin, and skeletal muscle was assessed 3 hours after either intravenous, oral, or intrauterine administration of 5-aminolevulinic acid with use of spectrophotofluorometry. In another experiment the fluorescence of surgically induced endometriosis and adjacent normal peritoneum was evaluated every 15 minutes after 5-aminolevulinic acid administration to assess the time course of protoporphyrin IX production. RESULTS In the rat endometriosis model intralesional and systemic 5-aminolevulinic acid produced fluorescence within implants showing viable endometrial cells. Treatment with 5-aminolevulinic acid produced low-intensity fluorescence in peritoneum, bowel mesentery, and eye. Relatively intense fluorescence was seen in skin, bladder, and uterus. No fluorescence was observed in skeletal muscle. The intensity of fluorescence varied with the dosage and route of administration of 5-aminolevulinic acid. Fluorescence intensity of protoporphyrin IX was significantly greater in implants than in adjacent normal peritoneum between 2 and 4 hours after treatment. CONCLUSIONS Protoporphyrin IX fluorescence in experimentally induced endometriosis lesions after intravenous and oral delivery of 5-aminolevulinic acid was significantly greater than the fluorescence detected in adjacent normal peritoneum.