Effects of ethanol during the onset of female puberty

To assess more closely the physiological mechanism(s) by which ethanol (ETOH) delays the onset of female puberty, we have evaluated its effects on body weight, the vaginal opening (VO)-first diestrus (D1) interval and the serum concentrations of growth hormone (GH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) throughout the peripubertal period in the rat. Using a specific intragastric feeding regimen, 29-day-old rats began receiving either a liquid diet containing ETOH or an isocaloric control liquid diet. Additional controls consisted of animals maintained on laboratory chow and water provided ad libitum. Animals were either killed between 32 and 37 days of age, categorized with regard to their phase of puberty and their serum hormones measured; or, in some animals, the ETOH liquid diet was administered through day 41 and at that time replaced by the control liquid diet in order to determine if recovery would occur. Our results indicate that ETOH-treated animals showed significantly lower body weights and a significantly longer mean VO-D1 interval than the control animals. Also, serum GH and LH levels were significantly lower in the ETOH-treated animals; however, FSH levels were not affected. Administration of the ETOH liquid diet through day 41 produced varying detrimental effects on the onset of puberty and subsequent removal of ETOH from the diet resulted in rapid growth of the animals, followed by the onset of puberty.(ABSTRACT TRUNCATED AT 250 WORDS)     

Essential fatty acid deficiency delays the onset of puberty in the female rat

This study assessed the effect of a dietary deficiency in the essential fatty acids (EFA) linoleic and linolenic acids on the onset of female puberty. EFA deficiency was produced in female rats by means of a semipurified diet and was biochemically documented by analyzing serum and erythrocyte fatty acid levels of more than 30 fatty acids, including all members of the n-6 and n-3 series. Levels of linoleic acid (18:2 n-6) and all n-6 derivatives, particularly arachidonic acid, were strikingly reduced. A less pronounced but clear-cut decrease in n-3 fatty acids, including docosahexaenoic acid (22:6 n-3) was also found. The times of puberty and first ovulation, as assessed by the ages at vaginal opening and first diestrus, were significantly delayed in EFA-deficient rats. The mechanisms underlying this delay appear to reside at both hypothalamic and ovarian sites. Simulation of preovulatory plasma estradiol (E2) levels via implantation of E2-containing Silastic capsules evoked a LH surge 30 h later in control juvenile rats, but not in EFA-deficient animals, indicating a delay in the development of the hypothalamic component of E2-positive feedback in the latter group. This delay appears to be due at least in part to reduced prostaglandin E2 (PGE2) synthesis, as the ability of the neurotransmitter norepinephrine to induce PGE2 release from median eminence nerve terminals was markedly reduced in EFA-deficient rats compared with that in controls. The decrease in hypothalamic PGE2 release was related to the EFA deficiency and not to reduced PG synthase activity, as determined by HPLC analysis of PG synthase products derived from exogenous [14C]arachidonic acid. Basal and hCG-stimulated PGE2 synthesis was also compromised in ovaries from EFA-deficient rats. Depressed gonadal function resulting from the EFA deficiency was further evidenced by a reduced gonadotropin receptor content, a blunted E2 response to hCG in vitro, and an increase in mean serum FSH levels. These results suggest that the delay in puberty resulting from EFA deficiency is due to a reduced availability of arachidonic acid for synthesis of bioactive metabolites. This results in delayed development of both the hypothalamic and ovarian components of the reproductive axis.     

Relation of biogenic amines to onset of puberty in the female rat.

Changes in hypothalamic concentration and turnover index (TI) of norepinephrine (NE), dopamine (DA), and serotonin (5HT) were studied during the first estrous cycle at the onset of puberty. Rats were killed when 40% of the population showed open vaginas. They were classified according to the state of their reproductive tract and serum LH values, as in anestrus, early proestrus, late proestrus, estrus, or diestrus. Serum LH, PRL, and hypothalamic LHRH were measured by RIA. The TIs for DA and NE were measured by estimating their rate of decrease after administration of alpha-methyl-para-tyrosine, and for 5HT-TI by its increase after pargyline administration. An increase in NE-TI in the hypothalamus was observed between anestrus and early proestrus, a decrease in DA-TI during early and late proestrus, and a small increase in 5HT-TI between early and late proestrus. LH and PRL peaks were observed at late proestrus when DA-TI and NE-TI reached their lowest values and hypothalamic LHRH concentration was failing. After late proestrus, the DA-TI rose sharply, NE-TI remained essentially unchanged. 5HT-TI fell, and serum LH and PRL declined to basal levels. These results suggest that the LH and PRL surges at late proestrus during the first estrous cycle at puberty are associated with an increase in NE-TI at early proestrus, a progressive decline in DA-TI at early and late proestrus, and an increase in 5HT-TI at late proestrus.     

Effects of adrenalectomy on the release of follicle-stimulating hormone and the onset of puberty in female rats

The involvement of the adrenal gland in the release of gonadotrophins and the onset of puberty in female rats was studied. Two and four days after adrenalectomy (ADX) on either day 5 or 10 after birth, a significant decrease in the concentration of FSH was found; 4 days after ADX on either day 15 or 20, FSH concentrations had increased significantly compared with sham-operated and/or intact controls. However, in the rats adrenalectomized on day 15 or 20, the body weights were lower than in control rats. Relative uterine weights (mg/100 g body wt) in adrenalectomized rats never differed from those of control rats. A delay in the time at which vaginal opening and the first oestrus occurred was found in rats adrenalectomized at 20 or 25 days of age; however this delay was accompanied in these rats by a retardation in the gain in body weight. It is argued that the effects of ADX on both the release of gonadotrophins and the onset of puberty are primarily, and presumably exclusively, due to the effects on general bodily development (expressed in body weight). The lack of effect of ADX on uterine weight supports the hypothesis that 'oestrogen-like' products from the adrenal gland are not biologically active as oestrogens.     

Changes in ovarian LHRH receptor content during the onset of puberty in the female rat

LHRH and some of its analogs have been reported to exert inhibitory effects on ovarian function, seemingly following interaction of the neurohormone with specific, high affinity binding sites. The present experiments were undertaken to determine whether LHRH binding sites in the ovary undergo quantitative changes during the onset of puberty in the rat. Changes in LHRH receptor content were assessed by the binding of the stable LHRH analog, [D-Ala6, Pro9]-LHRH to ovarian membrane preparations. LHRH binding in prepubertal rats (anestrus, A) was 166 +/- 11 fmol/mg protein, declined gradually (to 127 +/- 14 fmol/mg protein) during the early proestrous (EP) phase of puberty--a time at which intrauterine fluid begins to accumulate and uterine weight increases more rapidly--and became even lower (75 +/- 4 fmol/mg protein) by 1300 h of the day of first proestrus (LP), prior to the initiation of the first gonadotropin surge. At the time of the surge (1600 h) binding was 70 +/- 3 fmol/mg protein. LHRH binding was minimal on the day of the first estrus (E) and increased slightly on diestrus (D). The results indicate that the ovarian steroidogenic activation that precedes the first surge of gonadotrophins in the rat is associated with a marked loss in ovarian LHRH receptor content and suggest that a reduction in LHRH inhibitory function within the ovary may be a contributing factor to the pubertal enhancement in ovarian secretory activity.     

Effects of chronic thyroid hormone administration on pregnancy, lactogenesis and lactation in the rat.

We studied the effects of daily administration of 1 mg/kg thyroxine (T4) starting 10-15 days before mating, on parturition, maternal behavior and lactation in rats. Treated rats had elevated serum titers of T3 and T4, a greater number of fetuses and parturition was advanced approximately 12 h and lasted longer than in controls. None of the treated rats were able to lactate because of defects in maternal behavior and milk ejection; the litters died usually within 48 h postpartum. In rats sacrificed at 10.00 on day 21 of pregnancy, mammary gland content of total protein, phospholipids, casein and lactose were significantly increased, but total lipid was markedly reduced. Lipogenesis was also significantly increased, as well as the activity of the lipogenic enzymes glucose-6-phosphate dehydrogenase, fatty acid synthetase and isocitrate dehydrogenase. These results are indicative of normal albeit premature lactogenesis. The T4-treated rats also had advances in the prepartum fall in serum progesterone and the increase in prolactin as well as in the increase in mammary casein and lactose concentrations of approximately 12 h with respect to control pregnant rats. These results show that chronic T4 treatment induces an advance of approximately 12 h in luteolysis, which in turn advances lactogenesis and parturition in rats. Although the mammary gland was able to produce milk, lactation failed due to abnormal maternal behavior and milk ejection, the causes of which are still unknown. Other effects of hyperthyroidism were also present, such as a severe reduction in lipid content of the gland.(ABSTRACT TRUNCATED AT 250 WORDS)     

A reassessment of leptin's role in triggering the onset of puberty in the rat and mouse.

Leptin is an adipocyte-derived hormone that has been implicated to serve as a metabolic signal to the reproductive axis. The role of leptin in pubertal maturation, however, has been a much-debated topic. We have previously reported that leptin serves as a permissive signal to the onset of puberty in the female rat. In an attempt to further understand the mechanics of leptin during pubertal maturation in rodent species, we had three experimental objectives: first, to describe the temporal relationship of leptin with development in the male and female rat; second, to seek evidence for an increase in responsiveness of the neuroendocrine axis to leptin by assessing for possible changes in leptin receptor expression during pubertal developmental in the female rat; and, third, to reevaluate the possible role of leptin as a permissive signal to the onset of puberty in the mouse. We found that serum leptin levels remain relatively constant during the prepubertal and postpubertal stages of both sexes. In addition, we could not detect any significant developmental changes in leptin receptor gene expression in the hypothalamus of the female rat. Lastly, we corroborated our findings in the female rat that leptin reversed the delay in pubertal maturation secondary to food restriction but did not advance the onset of puberty in female mice. Together, these results suggest that leptin is not a metabolic trigger for the onset of puberty in the rodent; instead, leptin is one of several permissive factors, whose presence may be necessary but alone is not sufficient to initiate sexual maturation in these species.     

Effects of rat alpha-fetoprotein administration on estradiol free fraction, the onset of puberty, and neural and uterine nuclear estrogen receptors.

The cause of the onset of puberty in the rat or any other mammalian species is unknown. According to one theory, puberty is initiated through switching of the brain "gonadostat." It is hypothesized here that puberty in the rat is the consequence of the appearance of free, and therefore physiologically active, estrogen in the circulation. To test this, the unbound fraction of estradiol in serum of immature female rats was measured in relation to the nuclear receptor occupancy of estradiol in the hypothalamus, preoptic area, and uterus at various times after birth. In addition, an attempt was made to alter the free fraction of estradiol by injection of the estradiol-binding protein alpha-fetoprotein (AFP) into immature female rats. The free fraction of estradiol was low (less than 1%), but began rising at about 20 days of age, and a significant increase in nuclear bound estradiol was observed in 23-day-old rats (P less than 0.001). By day 30, unbound levels attained adult values (3.99 +/- 0.15%). At this time, nuclear bound estradiol in all tissues examined fell (P less than 0.01), but by day 40, these were greatly increased in rats in estrus (P less than 0.001), being trebled in the preoptic areas and doubled in the hypothalamus. Injection of AFP into immature female rats extended the period of low free estradiol (1.22 +/- 0.08%), while in albumin-injected rats, the free fraction was 4.44 +/- 0.1%. Injection of AFP resulted in levels of nuclear-bound estradiol that were less than half those measured in nuclei from AFP-injected animals (P less than 0.001), and AFP delayed puberty. The affinity of the reaction between estradiol and nuclear receptors in brains of immature and mature rats was not significantly different; the Kd fell within the range of 0.05-0.08 nM. It is suggested that in the rat, puberty is the result of the appearance in the circulation of physiologically active estradiol after day 20.     

Neuroendocrine mechanisms controlling the onset of female puberty: the rat as a model

The advent of female puberty represents the culmination of a diversity of developmental processes which affect all components of the reproductive axis. Development of neuroendocrine reproductive functions proceeds in a harmonious and interrelated manner. No unique 'trigger' of puberty can be discerned, but rather puberty represents the climax of a cascade of events, finely interconnected throughout the continuum of sexual maturation. A resetting of the hypothalamic 'gonadostat' to steroid negative feedback appears to be a phenomenon associated with puberty, but not its cause. Although the central nervous system plays a pivotal role in the development of the ovary, it is the acquisition of ovarian ovulatory capacity which finally determines the timing of the first preovulatory surge of gonadotropins. In contrast to primates, development of the central component of estradiol positive feedback is an early event in the female rat. However, in most species--including the rat--amplification (or initiation) of a particular, synchronous pattern of LHRH release appears essential for the initiation of puberty. The mechanisms underlying this functional change of the LHRH secreting system are not clearly understood. In the rat, ovarian development proceeds under the influence of gonadotropins, and the somatomammotropins PRL and GH. More intriguingly, evidence is now emerging that the central nervous system may convey direct information to the ovary via the ovarian nerves, thus providing a hormone-independent fine tuning for its control. Upon reaching adequate development, the ovary through its secretory products, acts on an already competent hypothalamic-pituitary axis to activate the central component of estradiol positive feedback.     

Effects of pregnancy on the onset and progression of diabetic nephropathy and of diabetic nephropathy on pregnancy outcomes

Controversy exists regarding the effect of pregnancy on the development and course of diabetic nephropathy. This study followed 43 pregnant women with previous diabetes mellitus, 32 without nephropathy (Group I) and 11 with nephropathy (Group II). Urinary albumin excretion (UAE), serum creatinine (Cr) and creatinine clearance (CCr) in the pre-pregnancy (Pre-P), first trimester (1T), third trimester (3T) and 1 year postpartum (PP) were evaluated. In both groups there were an increase in 3T compared to Pre-P of CCr (137 vs. 98 ml/min and 110 vs. 81 ml/min, p = 0.0001, respectively) and UAE (7.78 vs. 3.15 mg/24 h and 592 vs. 119 mg/24 h, p = 0.0001, respectively). Increase of Cr in the PP compared to 1T in Group II (0.88 vs. 0.70 mg/dL, p = 0.031) was observed. There were no difference in UAE, CCr and Cr in the PP when compared to pre-P as well variance over time between groups. Group II showed higher prevalence of chronic hypertension (72.7 vs. 21.9%, p = 0.004), preeclampsia (63.6 vs. 6.3%, p = 0.0003) and lower gestational age at birth (36 vs. 38 weeks, p = 0.003). We conclude that pregnancy was not associated with development and progression of diabetic nephropathy in women with or without mild renal dysfunction. The presence of diabetic nephropathy was associated with increased risk of perinatal complications.     

Chronic activation of dopamine receptors in the female infantile rat: effect on hypophyseal hormones and on the onset of puberty

In the female rat the period from days 7-20 of age is special with regard to regulation of hypophyseal hormone secretion. This period is characterized by high FSH levels and the occurrence of sporadic LH peaks. As it has been reported that haloperidol could enhance both gonadotropins at 12 days of age and not at later ages, it was of interest to treat rats during the infantile period with pergolide, a dopaminergic agent of long action, and evaluate its effect on hormone levels and puberty onset. Three different schedules of drug injections were applied: 1) daily injections (0.05 mg/kg.day) on days 1-10, 2) daily injections on days 5-14, and 3) daily injections on days 11-20. It was found that only animals treated with daily injections of pergolide on days 11-20 showed an advance in the age of vaginal opening and first estrus compared to distilled water-injected controls. Thus, the rest of the experiments were performed using injection schedule 3. In this group of animals serum LH and FSH levels were decreased 3 and 6 days after the beginning of pergolide treatment (13 and 16 days of age); at 19 days of age pergolide did not modify gonadotropin levels. One day after the end of pergolide treatment (day 21 of age), there was a rebound in LH levels in drug-injected rats, and a nonsignificant increment in FSH levels was observed. There were no differences in serum gonadotropin levels on days 22, 23, and 25 or peripubertally (29, 33, or 36 days of age). On the other hand, pergolide did not significantly modify PRL levels during the treatment, probably due to the already low values of PRL at these ages. Furthermore, PRL levels were not different between control and pergolide-injected rats at all other ages studied. After puberty onset, animals were observed for eight consecutive cycles, and both groups cycled regularly. Furthermore, PRL and gonadotropins levels were similar at diestrus and proestrus. To evaluate if pergolide treatment during the infantile period had caused permanent alteration in dopamine receptor sensitivity, animals were injected with haloperidol (0.1 or 0.25 mg/kg), and PRL release was evaluated. There were no differences in the hyperprolactinemic effect of the drug between groups. Finally, gonadotropin sensitivity to LHRH was similar in adult female rats in proestrus of both groups. The present results suggest that chronic activation of dopamine receptors during the infantile period evokes specific responses on gonadotropin secretion and advances the age of puberty onset.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neurobiological mechanisms of the onset of puberty in primates

An increase in pulsatile release of LHRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in LHRH release is still unclear. In primates the LHRH neurosecretory system is already active during the neonatal period but subsequently enters a dormant state in the juvenile/prepubertal period. Neither gonadal steroid hormones nor the absence of facilitatory neuronal inputs to LHRH neurons is responsible for the low levels of LHRH release before the onset of puberty in primates. Recent studies suggest that during the prepubertal period an inhibitory neuronal system suppresses LHRH release and that during the subsequent maturation of the hypothalamus this prepubertal inhibition is removed, allowing the adult pattern of pulsatile LHRH release. In fact, y-aminobutyric acid (GABA) appears to be an inhibitory neurotransmitter responsible for restricting LHRH release before the onset of puberty in female rhesus monkeys. In addition, it appears that the reduction in tonic GABA inhibition allows an increase in the release of glutamate as well as other neurotransmitters, which contributes to the increase in pubertal LHRH release. In this review, developmental changes in several neurotransmitter systems controlling pulsatile LHRH release are extensively reviewed.     

GPR54和kisspeptins与青春期启动

G蛋白偶联受体54(GPR54)和kisspeptins是哺乳动物体内的两组肽类物质,kisspeptins是 GPR54的配体,二者与青春期启动密切相关。大鼠GPR54突变者不能进入青春期,人类GPR54突变者出现性腺功能低下。动物实验表明,kisspeptins通过GPK54引起促性腺激素释放增加,可能直接作用于下丘脑促黄体激素释放激素神经元水平。     

Delayed puberty induced by chronic suppression of prolactin release in the female rat

To study the effect of PRL deficiency on the onset of puberty, PRL release was chronically inhibited by treating immature female rats with the dopaminergic receptor agonist, bromoergocriptine (CB-154). The resulting alterations in the time of puberty onset, and in other associated parameters, such as serum levels of pituitary hormones, ovarian responsiveness to gonadotropins and ovarian hCG receptor content were then evaluated. CB-154 was provided in the drinking water from day 22 onward at the concentration of 20 and 100 micrograms/ml. The treatment resulted in almost complete suppression of serum PRL levels throughout the entire period studied (day 22 to first diestrus). In contrast, serum GH, FSH, and LH levels were not depressed. Likewise, pulsatile release of FSH was not affected and only a subtle alteration in pulsatile LH release was apparent. The onset of puberty, as determined by the age at vaginal opening, and at first diestrus after the first estrus and by the presence of corpora lutea at sacrifice (first diestrus), was markedly delayed in the hypoprolactinemic (HPO) rats. This inhibitory effect of CB-154 was completely prevented by concomitant administration of PRL. Ovarian weight was significantly decreased in HPO rats at the three ages studied (27, 32, and 36 days of age). By day 36, 50% of the control animals had already ovulated, as compared with only 9% of the HPO rats. Microscopic examination of ovaries from HPO rats revealed a retarded follicular development. In vitro ovarian progesterone response to hCG studied at day 32 and 36 of age was reduced in the HPO rats. Uterine growth was also depressed in HPO rats, the ovaries of which, when incubated in vitro, failed to show the prepubertal increase in estrogen response to hCG seen in control rats between day 32 ad 36. Aromatase activity, as measured by the in vitro release of estradiol from ovaries incubated in the presence of an excess of androgen substrate, was depressed in HPO rats. hCG receptor content in the ovaries from HPO rats (counts per min [125]hCG bound per micrograms DNA) was also lower than that of control animals at day 32 and 34 but not at day 36. However, at this later time the hCG receptor content per milligram of ovary was still significantly reduced in HPO rats. The results support the view that PRL plays an important role in the process of ovarian development that leads to the onset of puberty in the female rat and that this effect is, at least in part, exerted through a positive influence of PRL on ovarian LH receptor content.     

Comorbidity in rheumatoid arthritis of early onset. Effects on outcome parameters

Three-year follow-up data of 1,032 patients with recent onset rheumatoid arthritis (RA) were analyzed regarding the frequency of 21 common comorbid chronic conditions and their impact on health outcome (i.e., pain, functional capacity, disease activity, and radiographic joint damage). Multivariate logistic regression analyses were used to calculate age- and gender-adjusted odds ratios for each chronic condition on severe functional capacity (<60% of full function). Comorbidity was already common at the onset of RA, with 72% of the patients having at least one comorbid condition and almost 50% having at least two. Common comorbidities were associated with significantly worse baseline measures in at least three of seven investigated outcome parameters. The more of these conditions patients had, the worse their 3-year outcome. Functional capacity was most sensitive to comorbid conditions. In logistic regression, obesity, hypercholesterolemia, type II diabetes, and osteoporosis resulted in a twofold risk of severe functional limitation (<60% of full function), independent of each other and of age and gender. The impact of comorbidity on measures of disease severity should be considered when used to compare outcome parameters of different RA samples.