The nipple: a simple intersection of mammary gland and integument, but focal point of organ function.

Having glands that secrete milk to nourish neonatal offspring characterizes all mammals. We provide a brief overview of the development and anatomy of nipples and mammary glands in monotremes, marsupials, and marine mammals, and focus on the nipples and mammary glands in terrestrial eutherian species. We first classify eutherians into three groups: the altricial, precocial, and arboreal types based on their rearing system. We then summarize the physiology of lactation and the cell biology of nipples with specific focus on comparing these in the mouse, cow, and human, which represent the three different groups. Finally we propose that the nipple is an example of specialized epidermis. As specialized epidermis, it is dependent the underlying stroma for development and maintenance in adult life. The development of the nipple and signaling pathways that regulate its formation are described.

Defining the kinetics of breast pseudoptosis after reduction mammaplasty.

Despite the clinical relevance of bottoming out, or pseudoptosis, associated with reduction mammaplasty (RM) its evaluation remains an imprecise science. This study aims to further define the kinetics of postoperative pseudoptosis over an extended period of time, after our previous study investigating pseudoptosis in the early postoperative period. Patients undergoing medial pedicle RM had 3-dimensional photographs taken at year 1 and year 2 intervals postoperatively (year 1 = 300-450 days; year 2 = 700-900 days). Bottoming out was assessed with various 3-dimensional parameters. The total breast volume and the percent tissue distribution in the upper pole of the breast did not change from year 1 to year 2. The anterior-posterior projection as well as vector measurements for internipple distance and sternal notch to nipple distance also remained stable from year 1 to year 2. Although previous data from our group documented the occurrence of bottoming out and continued size reduction over the first postoperative year after breast reduction, the present study shows that pseudoptosis does not seem to occur during the second postoperative year.

Endocrine-disrupting activities in vivo of the fungicides tebuconazole and epoxiconazole.

The triazole fungicides tebuconazole and epoxiconazole were investigated for reproductive toxic effects after exposure during gestation and lactation. Rats were dosed with epoxiconazole (15 or 50 mg/kg bw/day) or tebuconazole (50 or 100 mg/kg bw/day) during pregnancy from gestational day (GD) 7 and continued during lactation until postnatal day (PND) 16. Some dams were randomly chosen for cesarean section at GD 21 to evaluate effects on sexual differentiation in the fetuses. Other dams delivered normally, and the pups were examined (e.g., anogenital distance [AGD] and hormone levels) at birth, at PND 13 or PND 16, and semen quality was assessed in adults. Both tebuconazole and epoxiconazole affected reproductive development in the offspring after exposure in utero. Both compounds virilized the female offspring as shown by an increased AGD PND 0. Furthermore, tebuconazole had a feminizing effect on male offspring as shown by increased nipple retention. This effect was likely caused by the reduced testosterone levels seen in male fetuses. Tebuconazole increased the testicular concentrations of progesterone and 17alpha-hydroxyprogesterone in male fetuses, indicating a direct impact on the steroid synthesis pathway in the Leydig cells. The high dose of epoxiconazole had marked fetotoxic effects, while the lower dose caused increased birth weights. The increased birth weights may be explained by a marked increase in testosterone levels in dams during gestation. Common features for azole fungicides are that they increase gestational length, virilize female pups, and affect steroid hormone levels in fetuses and/or dams. These effects strongly indicate that one major underlying mechanism for the endocrine-disrupting effects of azole fungicides is disturbance of key enzymes like CYP17 involved in the synthesis of steroid hormones.

Prenatal testosterone exposure permanently masculinizes anogenital distance, nipple development, and reproductive tract morphology in female Sprague-Dawley rats.

In mammals, abnormal increases in fetal androgens disrupt normal development of the female phenotype. Due to the recent concern regarding environmental androgen-active chemicals, there is a need to identify sources of fetal androgen variation and sensitive developmental markers for androgenic activity in female rats. Anogenital distances (AGD), nipple retention, reproductive tract, and external genitalia are morphological parameters organized by prenatal androgens and are predictive of altered masculinized/defeminized phenotype in adult female mice and rats. The objectives of this study were to (1) characterize the natural prenatal androgen environment of rats including the magnitude of the intrauterine position (IUP) effect, (2) characterize the permanent effects of prenatal androgen exposure on female rats, and (3) determine the ability of AGD and areolas to predict these permanent androgenic alterations in female rats. Untreated male fetal rats had higher tissue testosterone (T) concentrations than females in the amniotic fluid, reproductive tract, gonad, and fetal body. The intrauterine position (IUP) of male and female fetuses did not affect T concentrations or AGD in male or female rats at gestational day (GD) 22. Female offspring exposed to 0, 1.5, and 2.5 mg/kg/day testosterone propionate (TP) on GDs 14-18 displayed increased AGD at postnatal day (PND) 2 and decreased nipples at PND 13 and as adults. TP-induced changes in neonatal AGD and infant areola number were reliable indicators of permanently altered adult phenotype in female rats. Further, females in the two high-dose groups displayed increased incidences of external genital malformations and the presence of prostatic tissue, not normally found in female rats.

In utero exposure to the environmental androgen trenbolone masculinizes female Sprague-Dawley rats.

Recently, the occurrence of environmental contaminants with androgenic activity has been described from pulp and paper mill effluents and beef feedlot discharges. A synthetic androgen associated with beef production is trenbolone acetate, which is used to promote growth in cattle. A primary metabolite, 17beta Trenbolone (TB), has been characterized as a potent androgen in both in vitro and in vivo studies with rats. The current study was designed to characterize the permanent morphological and functional consequences of prenatal TB exposure on female rats compared with those produced in an earlier study with testosterone propionate (TP). Female rat offspring were exposed to 0mg/day, 0.1mg/day, 0.5mg/day, 1.0mg/day, or 2.0mg/day TB on gestational days 14-19. The 0.5mg/day, 1.0mg/day, or 2.0mg/day TB groups displayed increases in neonatal anogenital distance (AGD) which persisted in the high dose group. Puberty was delayed in the high dose group and there were increased incidences of external genital malformations and the presence of male prostatic tissue in the 0.5mg/day, 1.0mg/day, or 2.0mg/day groups. These changes were associated with amniotic fluid concentrations of TB that compare favorably with concentrations known to be active in both in vitro systems and in fish.

The burden of gynecomastia among men on antiretroviral therapy in Zomba, Malawi.

BACKGROUND: Many Africans who are on life-saving ART face challenges from a variety of toxicities. After the introduction of a standardized first-line efavirenz-containing ART regimen, reports of gynecomastia appeared in Malawian popular media, however data on the prevalence and risk factors of gynecomastia from Africa are lacking. METHODS: We conducted a cross-sectional study in males ≥18 years registered on ART at the HIV clinic in Zomba Central Hospital. Men who reported to have ever experienced breast or nipple enlargement received a standard questionnaire and underwent physical examination. Questions included perceptions and concerns about gynecomastia. Clinicians confirmed the presence and severity of gynecomastia. Routinely collected data on current and previous ART regimens, CD4 count, WHO clinical stage, anthropometric measurements and history of tuberculosis were extracted from the electronic database. RESULTS: We enrolled 1,027 men with median age 44 years (IQR: 38-52). The median ART duration was 57 months (IQR: 27-85); 46.7% were in WHO stage III/IV at ART initiation, 88.2% had exposure to efavirenz and 9% were overweight or obese. The prevalence of self-reported gynecomastia was 6.0% (62/1027) (95%-CI: 4.7-7.7%). Of men with gynecomastia 83.6% reported nipple enlargement and 98.4% enlarged breasts (85.5% bilateral). One-third said they had not reported gynecomastia to a health care worker. Over three-quarters mentioned that gynecomastia was an important or very important problem for them, while more than half were embarrassed by it. On examination gynecomastia was present in 90% (confirmed gynecomastia prevalence 5.5%; 95%-CI: 4.2-7.0%) and 51.8% had severity grade III or IV. History of tuberculosis treatment was independently associated with self-reported gynecomastia, adjusted OR 2.10 (95%-CI: 1.04-4.25). CONCLUSIONS: The burden of gynecomastia among men on ART in Malawi was higher than previously reported, and was associated with adverse psychological consequences, calling for increased awareness, a proactive diagnostic approach and diligent clinical management.

The relaxin gene-knockout mouse: a model of progressive fibrosis.

Relaxin is well known for its actions on collagen remodeling. To improve our understanding of the physiologic role(s) of relaxin, the relaxin gene-knockout (RLX-KO) mouse was established by our group and subsequently phenotyped. Pregnant RLX-KO mice underwent inadequate development of the pubic symphysis as well as the mammary glands and nipples compared to wild-type mice, thus preventing lactation. Later studies showed that these deficiencies were associated with increased collagen, primarily in the nipple and vagina. Analysis of male RLX-KO mice also demonstrated inadequate reproductive tract development. The testis, epididymis, and prostate of RLX-KO mice showed delayed tissue maturation and growth associated with increased collagen deposition. In nonreproductive tissues, an age-related increase in interstitial collagen (fibrosis) was also detected in the lung, heart, and kidneys of RLX-KO mice and was associated with organ dysfunction. From 6-9 months of age and onwards, all organs of RLX-KO mice, particularly male mice, underwent progressive increases in tissue weight and collagen content (all P < .05) compared with wild-type animals. The increased fibrosis contributed to bronchiole epithelium thickening and alveolar congestion (lung), atrial hypertrophy and increased ventricular chamber stiffness (heart) in addition to glomerulosclerosis (kidney). Treatment of RLX-KO mice with recombinant human relaxin in early and developed stages of fibrosis caused the reversal of collagen deposition in the lung, heart, and kidneys. Together, these findings suggest that relaxin is a naturally occurring inhibitor of collagen deposition during normal development, aging, and pregnancy and can be used to prevent the progression of fibrosis.

Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring.

Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptors, agonizes the Ah receptor, and inhibits aromatase activity. In vivo prochloraz acts antiandrogenically in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing luteinizing hormone (LH) levels. The purpose of this study was to investigate reproductive toxic effects after exposure during gestation and lactation to prochloraz alone and a mixture of five pesticides (deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl). Prochloraz (30 mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from gestational day (GD) 7 until postnatal day (PND) 16. Some dams were taken for cesarean section at GD 21, and others were allowed to give birth. Results showed that prochloraz and the mixture significantly reduced plasma and testicular testosterone levels in GD 21 male fetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. Chemical analysis of the rat breast milk showed that prochloraz was transferred to the milk. In males a significant increase of nipple retention was found, and the bulbourethral gland weight was decreased, whereas other reproductive organs were unaffected. In addition cytochrome P450 (CYP)1A activities in livers were induced by prochloraz, possibly as a result of Ah receptor activation. Behavioral studies showed that the activity level and sweet preference of adult males were significantly increased. Overall these results strongly indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis.

Lack of evidence for endocrine disrupting effects in rats exposed to fenitrothion in utero and from weaning to maturation.

Fenitrothion is a broad-spectrum organophosphate insecticide. Recently, it has been reported to exert androgenic or anti-androgenic activity in in vitro and in vivo screening assays, although the effects appear equivocal in vivo. To provide a conclusive and comprehensive evaluation of fenitrothion, especially regarding its anti-androgenic activity in the reproductive and endocrine systems, we conducted a one-generation reproductive toxicity study at appropriately toxic dose levels with a number of sensitive endpoints for endocrine disruption. Fenitrothion was administered to Crj:CD(SD)IGS parental animals (P) at concentrations of 10, 20, and 60 ppm in the diet for 10 weeks prior to mating, and throughout mating, gestation and lactation. Their offspring (F1) were exposed from weaning until maturation at the age of 10 weeks. In the P generation, brain cholinesterase activity was remarkably reduced in the 60 ppm males and in the 20 and 60 ppm females. Reproductive performance, organ weights, histopathology, and sperm analytical parameters were not affected. In the F1 generation, no general toxicity or effects on anogenital distance, retention of areolae/nipples, onset of puberty, organ weights, histopathological findings, and sperm parameters were observed. In conclusion, fenitrothion had no effects on the reproductive or endocrine systems of the P and F1 generations, even at toxic doses that markedly suppressed brain cholinesterase activity in P animals. The results suggest that fenitrothion at in-use levels in the environment is unlikely to cause disruption of human endocrine systems.

Changes in testicular and nipple volume related to age and seasonality in Japanese macaques (Macaca fuscata), especially in the pre- and post-pubertal periods.

We investigated, longitudinally and cross-sectionally, age and seasonal change in both the testis and nipple volume of Japanese macaques (Macaca fuscata) in relation to concentration profiles of gonadal steroids: testosterone (T) in males and progesterone (P) in females. Testicular volume (TV) and nipple volume (NV) showed rapid growth at puberty, 4.5 and 3.5 years of age in males and females, respectively, but in both sexes there were precocious individuals. The testis as a whole matures at about 10 years of age. TV change is closely related to T concentration profile. The pattern of TV change is composed of maturation and seasonal effects, with individual variation evident mainly in the latter. Some individuals show a simple pattern consisting of one peak in the breeding season (from summer to winter) and one trough in the non-breeding season. Other individuals exhibit a more complicated pattern composed of two or more peaks and troughs before and during the breeding season. The nipple matures at about 7 years but it is difficult to determine the exact maturational age as there are many confounding factors relating to NV. NV shows seasonal fluctuations similar to that of TV. Many animals have periods of substantial growth whereas others do not. The NV in adults from 10 to 25 years does not appear to change much with age, but animals older than 25 years of age have significantly smaller nipples. Seasonal fluctuation in NV mirrors that of the P level. Considered to be controlled by estrogen and P, the NV is a good indicator of the physiological status of reproduction, with its peak about 2 weeks earlier than that of P, that is, at the mid-follicular phase. NV and P level show a similar pattern in pregnancy; from conception, indicated by a P peak, NV and P concentration first decrease, then they increase until peri-parturition and slowly decrease again until the next breeding season.

Nipple (papilla) development in puberty: longitudinal observations in girls.

The purpose of this study was to determine the manner of breast nipple (papilla) development occurring during puberty in girls on a longitudinal basis and to compare this development to the established criteria of sexual maturation. Forty-six girls (19 white and 27 black) were followed for periods of 2 to 5 years (mean 2.67 years). In each, the nipple diameter was measured and the Tanner stage assessed. Minimal nipple development occurred from stages PH1 to PH3 (3.24 to 4.44 mm) and B1 to B3 (3.00 to 4.72 mm) or more than 1 year prior to menarche (3.75 mm). Significant growth occurred beyond stages PH3 (PH4 6.54 mm, PH5 8.98 mm) and B3 (B4 7.25 mm, B5 9.41 mm) and from less than 1 year prior to menarche to more than 1 year after menarche (5.92 mm for girls less than 1 year premenarche, 7.88 mm for girls in their first year after menarche, and 9.05 mm for girls more than 1 year beyond menarche). A more objective definition for breast stages B4 and B5, based upon nipple diameter, is now feasible. Thus, these data enhance the precision with which physiologic events occurring toward the close of puberty in girls can be studied.

Effects of exogenous estrogenic agents on pubertal growth and reproductive system maturation in female rhesus monkeys.

Concern has been raised that environmental contaminants with estrogenic properties can alter normal sexual maturation. Monkeys, like humans, undergo a long and complex period of development during adolescence, which makes them important models for understanding exogenous estrogen effects during this period. This study examined the consequences of treatment with estrogenic agents (methoxychlor, MXC, 25 and 50 mg/kg/day; diethylstilbestrol, DES, 0.5 mg/kg/day) given in the peripubertal period (6 months before and after the expected age at menarche) to female rhesus monkeys. These treatments increased estrogen activity of serum as determined with an in vitro estrogen receptor alpha (ERa) transcription assay. DES completely suppressed adolescent growth (weight and height) and menses in a reversible manner; smaller effects of MXC on the timing of growth and menarche were also detected. Both DES and MXC led to premature emergence of a secondary sex characteristic, reddening and swelling of skin, but retarded growth of the nipple. As evaluated by ultrasound after an 8-month recovery period, uterine size was not affected by exogenous estrogen, but there was some indication of increased incidence of ovarian cysts/masses in MXC- and DES-treated groups. Ovarian cyclicity, as reflected in urinary hormone metabolites, demonstrated shorter follicular stages in the MXC-treated monkeys. In conclusion, the data indicate that DES had a striking effect on adolescent maturation and that the estrogenic pesticide MXC also altered development during this period. The pattern of effects across agents and doses may be based on specifics of estrogenic action, such as relative ERalpha and ERbeta binding and activation. Long-term consequences of this disruption of pubertal development are being studied in this cohort of monkeys as adults.

Anterior hypothalamic lesions and pubertal development in female rhesus monkeys.

Electrolytic lesions were made in the anterior hypothalamus of 8 prepubertal female rhesus monkeys, aged 1.1-1.7 years. Six unoperated females served as controls. No effects were found of the lesions upon age and body weight at menarche or at first ovulation, as estimated by blood levels of progesterone and laparoscopic observations. From these findings it appears that the neural control of puberty in the female rhesus may not be exerted through the anterior hypothalamus, in contrast with the rat and ferret. Further, an attempt was made to identify biometric correlates of hormonal changes during puberty. Firstly, the well known dip in growth rate, about 0.4 years before menarche, was observed. Secondly, there was a marked spurt in growth of the nipples starting at 0.2 years before menarche. The close temporal association between accelerated nipple growth and menarche suggests that both of these developmental characteristics result from changes in (presumably ovarian) steroid hormone secretion.

Nipple and areola diameter in Turkish pubertal girls.

The nipple and areola diameter of 498 girls aged 8-17 years were studied with the aim of finding measurable criteria for sexual maturation, including breast and pubic hair development during female puberty. All measurements were made holding a transparent ruler on both sides by the same observer. The smaller of the two measurements was used in the analysis. Significantly nipple and areola development occurred between breast stages B1 (2.56 and 14.35 mm), B2 (3.32 and 20.26 mm), B3 (5.21 and 28.84 mm), and B4 (6.28 and 32.03 mm). The nipple and areola diameter were also significantly greater in pubic hair stage (PH)3 (5.05 and 25.24 mm) with respect to PH2 and PH1 (3.46, 2.62 mm and 19.32, 15.37 mm, respectively), in PH5 (6.79 and 35.62 mm) with respect to PH4 (6.55 and 32.56 mm). A significant increase in nipple and areola diameter occurs between premenarchal girls and girls older than 0-2 years postmenarche. Sexual maturation staging by nipple size and by areola size appears to be feasible for female adolescent. However, staging by nipple size does not appear to be feasible for B4 and B5 stage, because the incremental gradations are small.

Inhibin B, follicle stimulating hormone, luteinizing hormone, and estradiol and their relationship to the regulation of follicle development in girls during childhood and puberty.

Inhibin B, produced by granulosa cells in the ovary, is a heterodimeric glycoprotein suppressing synthesis and secretion of the follicle stimulating hormone (FSH). The aim of the present study was to determine hormone profiles of inhibin B, FSH, luteinizing hormone (LH), and estradiol in girls during childhood and puberty and to evaluate whether inhibin B is a marker of follicle development. We examined the correlation between inhibin B and gonadotropins and estradiol during the first two years and across the pubertal development. Using a specific two-side enzyme-linked immunosorbent assay (ELISA), inhibin B levels were measured in the serum of 53 healthy girls divided into 8 groups according to age. In addition, serum FSH, LH, and estradiol were measured by chemiluminescent immunoassay in all serum samples. A rise in serum levels of inhibin B (55.2+/-7.3 ng/l, mean +/- S.E.M.) and FSH (1.78+/-0.26 UI/l), concomitant with a moderate increment of serum LH (0.36+/-0.09 UI/l) and estradiol (45.8+/-12.2 pmol/l) concentrations was observed during the first three months of life and declined to prepubertal concentrations thereafter. A strong positive correlation between inhibin B and FSH (r = 0.48, p<0.05), LH (r = 0.68, p<0.001) and estradiol (r = 0.59, p<0.01) was demonstrated during the first 2 years of life. A rise in serum levels of inhibin B, FSH, LH, and estradiol was found throughout puberty. Inhibin B had a strong positive correlation with FSH (stage I of puberty: r = 0.64, p<0.05; stage II of puberty: r = 0.86, p<0.01), LH (I: r = 0.61, p<0.05; II: r = 0.67, p<0.05), and estradiol (II: r = 0.62, p<0.05) in early puberty. From pubertal stage II, inhibin B lost this relationship to gonadotropins and estradiol. Serum inhibin B and FSH levels increased significantly during pubertal development, with the highest peak found in stage III of puberty (133.5+/-14.3 ng/l), and decreased thereafter. In conclusion, inhibin B is produced in a specific pattern in response to gonadotropin stimulation and plays an important role in the regulation of the hypothalamic-pituitary-gonadal axis during childhood and puberty in girls. Inhibin B is involved in regulatory functions in developing follicles and seems to be a sensitive marker of ovarian follicle development.

Nipple development in female puberty.

Nipple diameters of 230 girls aged between 11-17 were calculated with the aim of finding measurable criteria for breast development during female puberty. There was a significant increment in nipple diameters in each breast and pubic hair stage with respect to the previous stages. The maximum increment was found to be from B 1 to B 2 (2.44 mm), and from PH 1 to PH 2 (2.69 mm). With respect to menstrual status, the greatest growth in nipple diameter occurred from the premenstrual period (M(-)) to one year postmenarche (M +1) (2.35 mm). These results are compared with other studies in the literature, and it was concluded that increments in nipple size in each pubertal stage is related to the hormonal status as well as to race, nutrition and genetics. More longitudinal and cross-sectional data are needed in order to find a measurable criteria for the Tanner breast stages.

[Effect of the father-daughter relationship on the morphological development of the mammary glands]. / Influencia de la relación Padre-Hija sobre el desarrollo morfológico de las glándulas mamarias.

The puberal development of the mammary glands is the result of a final increase of serum estradiol. Having observed that the relationship with the father can affect the concentration of estradiol in the serum, the authors studied the relationship between the intensity of that interaction and the morphological development of the breasts, a standing witness in a woman's body of the concentration of estradiol in the serum during the pubertal stage. The study had two parts: 1) The review of the clinical histories of 145 nulliparous women between 18 and 25 years of age. 57.3% lived with their fathers, while 42.6% had no father, either because of death or separation. The difference between both groups in breast size as well as in the width of the areola was significant. There was also a significant difference depending on whether the separation occurred before or after the girl was 9 years old. 2) The administration of a questionnaire to 90 nulliparous women between the ages of 18 and 25, to establish the intensity of the father/daughter relationship. The results showed significant differences between the intensity of the father/daughter relationship, breast size and width of the areola. There was no significant correlation between the intensity of the relationship and the pigmentation of the areola in either of the two phases.

Pilot study of normal development of nipples during pregnancy.

BACKGROUND: Numerous factors, both in the mother and in the infant, are involved in achieving breastfeeding. One maternal factor is normality of the nipples. However, no definition of normal nipple length or width or normal range and changes in pregnant women exists. OBJECTIVE: This study aimed to demonstrate the change of nipple length and width and areola width during pregnancy in Thai women. METHODS: This descriptive study was conducted from March 2010 to July 2011. A total of 56 pregnant women with nipple length ≥ 7 mm on both sides were recruited for the study. All women were at 8 to 12 weeks of gestation. The patients were scheduled for nipple and areola measurements up to 9 times, depending on the routine antenatal care appointments and delivery date. Nipple length and width and areola width of all participants were consecutively evaluated in each prenatal visit. RESULTS: The mean nipple length was 9.3 ± 1.5 mm at the first visit and significantly increased to 11.2 ± 1.8 mm by the time of the last visit (P < .001). Similarly, the nipple width was 13.6 ± 1.8 mm in the first trimester and widened to 15.9 ± 2.3 mm at term (P < .001). No differences of nipple length or width change were observed between both sides. The areola width of both sides considerably increased by 12.3 ± 6.1 mm during pregnancy (P < .001). CONCLUSION: During pregnancy, nipple length and width as well as areola width increased significantly.

Desenvolvimento sexual e maturação puberal / Sexual and puberal development

Os fenômenos do desenvolvimento sexual e puberal são eventos progressivos e coordenados. Dependem de fatores cromossômicos - gênicos, gonadais e hormonais. Tais eventos nos indivíduos do sexo masculino e feminino, sendo sincrônicos, permitirão um conveniente desenvolvimento sexual e puberal. Analisar tais fenômenos é o propósito deste estudo.(AU)

The sexual and puberal modifications are coordinate and progressive during differents life phases. Many factors are involved like genic-chromosomic, gonadal and hormonal. Those events that occurred in males and females are synchronous and to create a perfect development. Our proposal is review those situations.(AU)

Reduced expression of the PTH/PTHrP receptor during development of the mammary gland influences the function of the nipple during lactation.

Signaling by the parathyroid hormone/parathyroid hormone-related protein receptor (Ppr) is necessary for mammary gland development beyond the early induction stage in mice. We used a series of murine models of reduced Ppr expression to determine how diminished receptor signaling influences mammary development. Reduction of Ppr expression to very low levels prevented mammary gland development. A less-severe reduction in Ppr expression permitted progression of mammary gland development beyond the induction stage, but the nipples of these mice were dramatically smaller than those of controls, with altered epidermis and connective tissue. Mothers with reduced expression of Ppr could not successfully nurse pups; however, the lactating glands did produce milk but could not efficiently deliver it. This finding was associated with reduced levels of matrix metalloproteinase-2 and an absence of pregnancy-associated remodeling of connective tissue matrix in the nipple. Reduced smooth muscle appears to underlie the majority of nipple deficiencies in mice with lower levels of the Ppr expression.