Availability of recombinant growth hormone (GH) and development of long-acting formulations of this material will undoubtedly lead to widespread use of GH in animal industry and in medicine. GH can act, directly or indirectly, on multiple targets, but its influence on the reproductive system and on the hormonal control of reproduction is poorly understood. Overexpression of GH genes in transgenic animals provides a unique opportunity to study the effects of long-term GH excess. Transgenic mice overexpressing bovine, ovine, or rat GH (hormones with actions closely resembling, if not identical to, those of endogenous [mouse] GH), exhibit enhancement of growth, increased adult body size, and reduced life-span as well as a number of endocrine and reproductive abnormalities. Ectopic overexpression of bovine GH (bGH) driven by metallothionein or phosphoenolpyruvate carboxykinase promoters is associated with altered activity of hypothalamic neurons which produce somatostatin, loss of adenohypophyseal GH releasing hormone (GHRH) receptors, and suppression of endogenous (mouse) GH release. Elevation of plasma levels of GH (primarily bGH) and insulin-like growth factor (IGF-I) in these transgenic mice leads to increases in the number of hepatic GH and prolactin (PRL) receptors, in the serum levels of GH-binding protein (GHBP), in the percent of GHBP complexed with GH, and in the circulating insulin levels. In addition, plasma adrenocorticotropic hormone (ACTH) and corticosterone levels are elevated. Plasma levels of luteinizing hormone (LH), as well as its synthesis and release, are not consistently affected, but follicle-stimulating hormone (FSH) levels are suppressed, apparently due to pre- and post-translational effects. Pituitary lactotrophs exhibit characteristics of chronic enhancement of secretory activity, and plasma PRL levels are elevated. Prolactin responses to mating or to pharmacological blockade of dopamine synthesis are abnormal. Reproductive life span and efficiency are reduced in both sexes, with the severity and frequency of reproductive deficits being related to plasma bGH levels. Most transgenic females expressing high levels of bGH are sterile due to luteal failure. Overexpression of human GH which, in the mouse, interacts with both GH and PRL receptors leads to additional endocrine and reproductive abnormalities including stimulation of LH beta mRNA levels and LH secretion, loss of responsiveness to testosterone feedback, overstimulation of mammary glands, enhanced mammary tumorigenesis, and hypertrophy of accessory reproductive glands in males.

Reproductive performance was studied in transgenic males from lines expressing and transmitting four hybrid genes: mouse metallothionein-I/human growth hormone (GH) (MT/hGH), MT/hGH placental variant (MT/hGH.V), MT/bovine GH (MT/bGH) and phosphoenolpyruvate carboxykinase/bGH (PEPCK/bGH). Each male was exposed to three normal females for 1 week and to three different normal females for another week. Females were examined for vaginal plugs and necropsied on day 14 of pregnancy. Males were killed for analysis of organ weights, numbers of testicular spermatids, numbers of epididymal sperm and measurements of plasma glucose concentration. Fertility of MT/hGH and MT/hGH.V transgenic males was significantly lower than in normal males, primarily because most males failed to impregnate any females. In females that became pregnant, the numbers of corpora lutea, total fetuses and live fetuses did not differ from those in females mated to normal (nontransgenic) males. Fetal crown-rump length on day 14 of pregnancy did not differ between litters sired by normal or by transgenic males. Weights of testes and seminal vesicles were significantly greater in all four types of transgenic male, but daily sperm production per unit weight (g-1) of testis was not affected and epididymal sperm reserves were either normal or slightly higher than normal. Plasma glucose concentrations were significantly higher in PEPCK/bGH mice than in other mice. Average or individual reproductive performance of transgenic males from the various lines did not correlate with any of the parameters examined except for significantly heavier seminal vesicles in MT/hGH and MT/hGH.V males than in normal males; these transgenic males exhibited a high incidence of infertility. Since hGH and hGH.V, but not bGH, are lactogenic in rodents, it was concluded that chronic stimulation of GH and prolactin receptors by ectopically produced human GHs in transgenic mice compromises male fertility by an unknown mechanism. Reduced fertility of transgenic males with MT/hGH or MT/hGH.V hybrid genes is due to failure to inseminate or impregnate females rather than to reduced numbers of spermatozoa or gross changes in the male reproductive system.

Both physiological and excessive levels of growth hormone (GH) can affect reproductive functions. Overexpression of human (h) or bovine (b) GH in transgenic female mice was previously reported to be associated with reproductive deficits. The objectives of the present study were to determine the age of onset of puberty, the length of the estrous cycle, and the ovulation rate in transgenic and normal mice from a line expressing bGH with the phosphoenolpyruvate carboxykinase (PEPCK) promoter and characterized by very high levels of transgene expression. Transgenic females reached puberty, defined as the appearance of the vaginal introitus, earlier than their normal littermates, but at a higher body weight. Compared to normal animals, an increased number of transgenic females failed to mate during the 15-day period of observation, and pregnancy rates were reduced. However, ovulation rates, as estimated by counting CL and implantation sites on Day 7 postcoitum, were increased in transgenic females. Plasma bGH levels in transgenic females ranged from 700 to 2200 ng/ml and were negatively correlated with fertility. To assess the effect of bGH on the ovulation rate in non-transgenic mice, normal females were paired with normal males and injected for up to 3 days with either 0.75 mg bGH/day or 0.30 mg bGH/day (injected as a single dose or as 0.15 mg twice daily). Data from animals that mated after at least 2 days of bGH treatment were analyzed. The ovulation rate was increased in females treated with 0.75 mg bGH/day, as compared to controls, and in females injected with 0.15 mg bGH twice daily as compared to those given 0.3 mg bGH/day and to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Ectopic expression of human or bovine growth hormone (GH) genes in 6 lines of transgenic mice was associated with a significant increase in plasma corticosterone levels. Elevated corticosterone levels were detected in both sexes under basal conditions and after ether stress. The adrenal activity of 3β-hydroxysteroid dehydrogenase was measured in two of these lines and was found to be significantly increased in transgenic animals. Plasma corticosterone levels in transgenic mice did not correlate with known differences between the various lines in male and female fertility or in the life span.

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Este estudo verificou a eficiência de infusão de duas plantas usadas na medicina popular, Syzygium jambolanum (Sj) e Bauhinia candicans (Bc). Sessenta (60) ratos adultos, machos, da linhagem Wistar, pesando entre 220 e 240g, foram submetidos à indução de Diabetes mellitus insulino dependente (DMID) com Aloxano. O estudo foi dividido em dois experimentos. No primeiro, 15 ratos receberam a administração de Aloxano na dosagem de 40mg/kg em dose única e no segundo, 60mg/kg uma vez ao dia, durante três dias, ambos por via intraperitonial. A hiperglicemia foi confirmada no terceiro dia de cada experimento. Após esta confirmação, os animais foram divididos aleatoriamente em três grupos de cinco e quinze animais para o primeiro e segundo experimento, respectivamente. O grupo 1 (C) serviu como controle, o grupo 2 (TI) recebeu infusão de Sj "ad libitum" como fonte líquida e o grupo 3 (TII) recebeu infusão de Bc, por um período de 21 e 40 dias, para o primeiro e segundo experimento, respectivamente. A colheita de sangue foi realizada por punção do plexo venoso retro-orbitário com os animais anestesiados, nos dias 3, 9, 16 e 23 do primeiro experimento e nos dias 3, 16, 24 e 40 do segundo. Após vinte e um dias da fase de tratamento, o grupo TI do primeiro experimento apresentou marcante redução de hiperglicemia (P < 0,001). Esta mesma observação foi verificada no grupo TI do segundo experimento aos dezesseis dias da fase de tratamento (P < 0,004), estendendo-se até os quarenta dias (P < 0,0001), quando comparado ao grupo controle. Simultaneamente, sinais clínicos de DMID, como polifagia e polidipsia foram reduzidos neste grupo. O colesterol plasmático demonstrou aumento moderado somente nos animais do segundo experimento, não sendo observado o efeito do tratamento com infusão Sj e Bc sobre a colesterolemia dos animais em estudo. No 40º dia de ambos os experimentos, os animais foram eutanasiados e foram colhidas amostras de pâncreas e fígado para avaliação histopatológica. A análise histopatológica das amostras de pâncreas e fígado do experimento I não demonstrou diferença entre os grupos tratados e o grupo C. No entanto, no experimento II, nove em dez amostras do grupo C e cinco em nove amostras do grupo TII apresentaram necrose de células das ilhotas de Langerhans do pâncreas, enquanto que somente duas das nove amostras do grupo TI apresentaram necrose de células das ilhotas de Langerhans. Os resultados obtidos neste estudo permitem concluir que o uso de infusão da planta Sj como substituto da água é eficiente no controle da hiperglicemia e redução dos sinais clínicos do DMID como polifagia e polidipsia, enquanto que o tratamento com infusão de Bc não possui o mesmo efeito.

Overexpression of growth hormone (GH) in transgenic mice is associated with various degrees of impairment of female reproductive functions. Transgenic PEPCK.bGH mice express high GH levels, and only around 20% of the females will carry gestation to Day 7. The objective of the present study was to investigate luteal function in PEPCK.bGH mice during early pregnancy, when CL are fully dependent on the pituitary. Plasma progesterone levels measured on Days 2 or 7 postcoitum (p.c.) were lower in transgenic than in normal females. In transgenic females with a previous history of infertility, daily injections of 1 mg progesterone starting on Day 2 p.c. significantly increased the proportion of animals pregnant on Day 7. When ovaries from transgenic mice were transplanted into ovariectomized normal littermates, the recipients exhibited normal vaginal cycles and responded to mating by vaginal cytology changes consistent with pseudopregnancy. In contrast, ovariectomized transgenic females bearing transplants of ovaries from normal mice had slightly prolonged estrous cycles and failed to become pseudopregnant after mating. Plasma progesterone levels on Days 2 and 7 p.c. in normal females with transgenic ovaries were not different from plasma progesterone levels measured in normal females into which normal ovaries had been transplanted. Twice-daily injections of 100 micrograms of prolactin (PRL) in saline or in polyvinylpyrrolidone starting on the evening of Day 2 p.c. were able to rescue luteal function. The proportion of PRL-injected transgenic animals that were pregnant on Day 7 was significantly higher than that of saline-injected transgenic controls and resembled the pregnancy rate of normal animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Transgenic mice carrying the phosphoenolpyruvate carboxykinase promoter region-human growth hormone (PEPCK-hGH) fusion gene are characterized by accelerated growth and plasma hGH levels ranging from 100 to 700 ng/ml. Both sexes are fertile, in contrast to previous findings in metallothionein-I/hGH transgenic mice in which females are sterile, apparently due to luteal failure. Virgin transgenic PEPCK/hGH females from this line produce milk and can successfully raise foster litters to weaning. We conclude that the life-long presence of very large amounts of hGH in the circulation is compatible with ovulation, can override the effects of hGH-induced suppression of endogenous PRL release, and can support full lactation in animals that have not been primed by hormonal changes associated with pregnancy.