Biotin deficiency and biotin excess: Effects on the female reproductive system

Biotin deficiency and biotin excess have both been found to affect reproduction and cause teratogenic effects. In the reproductive tract, however, the effects of biotin have not been well established yet. We investigated the effects of varying biotin content diets on the oestrus cycle, ovarian morphology, estradiol and progesterone serum levels, and the uterine mRNA abundance of their nuclear receptors, as well as on the activity of the estradiol-degrading group of enzymes cytochrome P450 (CYP) in the liver. Three-week-old female BALB/cAnN Hsd mice were fed a biotin-deficient, a biotin-control, or a biotin-supplemented diet (0, 7.2 or 400 μmol of free biotin/kg diet, respectively) over a period of nine weeks. Striking effects were observed in the biotin-deficient group: mice showed arrested estrous cycle on the day of diestrus and changes in ovary morphology. Estradiol serum concentration increased 49.2% in biotin-deficient mice compared to the control group, while the enzymatic activities of CYP1A2 and CYP2B2 increased (P < 0.05). The mRNA abundance of nuclear estrogen and progesterone receptors decreased in the biotin-deficient mice. In the biotin-supplemented group we found that, in spite of a significant (P < 0.05) decrease in the number of primary and Graafian follicles and in CYP1A2 activities, mice exhibited 105.4% higher serum estradiol concentration than the control group. No changes in the expression of the nuclear receptors were observed. No significant differences were observed in serum progesterone among the groups. Our results indicate that both the deficiency and the excess of biotin have significant effects on the female mouse reproductive system.     

Wnts and the female reproductive system.

Wnts are intercellular growth and differentiation factors that regulate several key developmental steps, such as gastrulation, neurulation, and organogenesis, including the development of the midbrain, central nervous system, kidney, and limbs. Wnts are also needed for a normal development of the reproductive system. Deficiency of Wnt-4, -5a, and -7a, for example, results in sex reversal, infertility, and/or malformation of the internal and external genitals. Here we focus on the importance of Wnts in the female reproductive system.     

Angiogenesis in the female reproductive system.

In adult tissues, capillary growth (angiogenesis) occurs normally during tissue repair, such as in healing of wounds and fractures. Rampant capillary growth is associated with various pathological conditions, including tumor growth, retinopathies, hemangiomas, fibroses and rheumatoid arthritis. The female reproductive organs (i.e., ovary, uterus, and placenta) exhibit dynamic, periodic growth and regression accompanied by equally dramatic changes in rates of blood flow. It is not surprising, therefore, that they are some of the few adult tissues in which angiogenesis occurs as a normal process. Thus, the female reproductive system provides a unique model for studying regulation of angiogenesis during growth and differentiation of normal adult tissues. Ovarian, uterine, and placental tissues recently have been shown to contain and produce angiogenic and anti-angiogenic factors. This review discusses the current state of knowledge regarding angiogenic processes and their regulation in female reproductive tissues. In addition, implications of this research for regulation of fertility as well as for control of angiogenesis in other normal and pathological processes are discussed.     

NPY: its occurrence and relevance in the female reproductive system

Neuropeptide Y (NPY), an amidated peptide composed of 36 amino acid residues, is the most widely distributed neuropeptide that performs a broad spectrum of physiological functions in both the central and peripheral nervous systems. Among numerous other actions, this peptide is involved, at the periphery, in the neural regulation of blood pressure and blood flow through the organs, and also, acting via Y2 and/or Y5 receptors, in the regulation of angiogenesis. NPY influences blood vessels via its own Y receptors, predominantly of the Y1 subtype. As a sympathetic co-transmitter NPY causes vasoconstriction, stimulates vascular growth and potentiates the contractile activity of noradrenaline (NA), and as a parasympathetic neurotransmitter it is involved in the regulation of vasodilatation within e.g. the uterine artery. In the female reproductive system, NPY not only regulates the blood flow, but also the contractile activity of non-vascular smooth muscle cells of the uterus and oviduct, as well as the secretory function of the ovary. Both the concentration of NPY and its influence on the blood flow through the female reproductive organs are finely tuned by fluctuations in the concentration of ovarian steroid hormones. Thus, the present review was aimed at summarizing the current knowledge dealing with the physiological relevance of NPY in the regulation of female gonad and genital tract function, with a special regard to the pig as a model animal.     

Schistosoma mansoni: praziquantel-induced changes to the female reproductive system

The long-term in vivo effects of a single subcurative dose (200 mg/kg body wt of mouse) of praziquantel on the ultrastructure of the female reproductive system of Schistosoma mansoni were investigated. Morphological changes in the structure of both the vitelline gland and the ovary were apparent within 24 hr post-treatment, and lead to a partial or complete regression of both organ systems. Associated with this regression was a cessation of egg production. In surviving, paired females, irrespective of the initial severity of the drug-induced damage, both the vitelline gland and the ovary completely redeveloped and lead eventually to a resumption of egg production. In contrast, in unpaired, previously mature females the reproductive system also regressed but did not redevelop. In these cases, although the initial changes in the reproductive system were the result of drug action, the long-term regressive changes were due to discontinued male stimulation.     

Effects of excess biotin administration on the growth and urinary excretion of water-soluble vitamins in young rats

To determine the effects of excess biotin administration on growth and water-soluble vitamin metabolism, weaning rats were fed on a 20% casein diet containing 0.00002% biotin, or same diet with 0.04, 0.08, 0.10, 0.20, 0.50, 0.80 or 1.0% added biotin for 28 days. More than 0.08% biotin administration decreased the food intake and body weight gain compared with the levels in control rats. An accumulation of biotin in such tissues as the liver, brain and kidney increased in a dose-dependent manner, and the both bound and free biotin contents in the liver also increased in a dose-dependent manner. An excess administration of biotin did not affect the urinary excretion of other water-soluble vitamins, suggesting no effect on the metabolism of other water-soluble vitamins. The results of the food intake and body weight gain indicated that the lowest observed adverse effect level for young rats was 79.2 mg/kg body weight/day, while the no observed adverse effect level was 38.4 mg/kg/day. These results suggested immediately setting a tolerable upper intake level for biotin.     

Effects of prenatal administration of testosterone and cortisone on the reproductive system of the female rat.

Testosterone propionate, cortisone, or sesame oil vehicle were given to rats during the last week of pregnancy so that effects of the hormones on anogenital distance, breeding capacity and vaginal opening of the female progeny could be contrasted. Testosterone significantly increased anogenital distance and delayed vaginal opening of progeny. When females that had been exposed to testosterone in utero were tested for breeding capacity, a significantly smaller number mated than in the control group. Female rats that had been exposed to cortisone in utero exhibited premature vaginal opening but did not differ from controls in anogenital distance, and, unlike the testosterone-exposed rats, mated. Cortisone-exposed rats carried litters to term and the litters did not differ from those of controls in numbers of pups or numbers of living pups at birth. The pups born to cortisone-exposed rats had greater birth weights and a higher survival rate to 20 days of age than pups of controls. Results indicate that testosterone administration to rats during pregnancy is far more detrimental to the development and subsequent function of the reproductive system of female progeny than cortisone and suggest that similar changes which occur in response to maternal stress or to administration of ACTH during pregnancy are more likely to result from increases in testosterone than from increases in glucocorticoid secretion.     

Depletion of biotin from brain and liver in biotin deficiency

The effects of biotin deficiency on the metabolism of glucose (Bhagavan, Coursin and Dakshinamurti, 1965; Bhagavan, Maruyama and Coursin, 1967; Bhagavan, Coursin and Stewart, 1969) and central nervous system function (Bhagavan, Stewart, Dakshinamurti and Coursin, 1966; Stewart, Bhagavan, Coursin and Dakshinamurti, 1966; Stewart, Bhagavan and Coursin, 1967 a, b ; 1968) have already been reported. In a study of the biochemical changes in the brain and other tissues of the rat in biotin deficiency, the depletion of biotin from the brain and liver during the course of the deficiency has been followed. We found that while the liver lost over 90 per cent of its biotin, the depletion from the brain was only about 50 per cent after 8 weeks on the deficient diet. These data comprise the present report.     

Tributyltin-induced imposex in stenoglossan gastropods: Pathological effects on the female reproductive system

• 1.1. The imposition of male sex organs on female stenoglossan gastropods—“imposex”—is a worldwide phenomenon now known to be associated with the usage of marine antifouling paints containing tributyltin (TBT) compounds.
• 2.2. The effect of the imposex response on the female reproductive system varies according to species: in some, breeding appears unaffected, whilst in others the anatomy of the oviduct may be so modified that the female is effectively sterilised.
• 3.3. New evidence suggests that TBT interrupts steroid metabolism, notably the conversion of testosterone to oestradiol 17β.

     

Effects of biotin deficiency on pancreatic islet morphology, insulin sensitivity and glucose homeostasis

Several studies have revealed that physiological concentrations of biotin are required for the normal expression of critical carbohydrate metabolism genes and for glucose homeostasis. However, the different experimental models used in these studies make it difficult to integrate the effects of biotin deficiency on glucose metabolism. To further investigate the effects of biotin deficiency on glucose metabolism, we presently analyzed the effect of biotin deprivation on glucose homeostasis and on pancreatic islet morphology. Three-week-old male BALB/cAnN Hsd mice were fed a biotin-deficient or a biotin-control diet (0 or 7.2 μmol of free biotin/kg diet, respectively) over a period of 8 weeks. We found that biotin deprivation caused reduced concentrations of blood glucose and serum insulin concentrations, but increased plasma glucagon levels. Biotin-deficient mice also presented impaired glucose and insulin tolerance tests, indicating defects in insulin sensitivity. Altered insulin signaling was linked to a decrease in phosphorylated Akt/PKB but induced no change in insulin receptor abundance. Islet morphology studies revealed disruption of islet architecture due to biotin deficiency, and an increase in the number of α-cells in the islet core. Morphometric analyses found increased islet size, number of islets and glucagon-positive area, but a decreased insulin-positive area, in the biotin-deficient group. Glucagon secretion and gene expression increased in islets isolated from biotin-deficient mice. Our results suggest that biotin deficiency promotes hyperglycemic mechanisms such as increased glucagon concentration and decreased insulin secretion and sensitivity to compensate for reduced blood glucose concentrations. Variations in glucose homeostasis may participate in the changes observed in pancreatic islets.     

Marginal biotin deficiency is teratogenic in mice and perhaps humans: a review of biotin deficiency during human pregnancy and effects of biotin deficiency on gene expression and enzyme activities in mouse dam and fetus

Recent studies of biotin status during pregnancy provide evidence that a marginal degree of biotin deficiency develops in a substantial proportion of women during normal pregnancy. Several lines of evidence suggest that although the degree of biotin deficiency is not severe enough to produce the classic cutaneous and behavioral manifestations of biotin deficiency, the deficiency is severe enough to produce metabolic derangements in women and may be teratogenic. In studies of mice, a similar degree of biotin deficiency induces characteristic fetal malformations at a high rate. Fetal hepatic biotin content and PCC activity decrease indicating that the fetuses also become biotin deficient. Fetal hepatic acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase and beta-methylcrotonyl-CoA carboxylase abundances determined by Western blotting decreased more than the dam holocarboxylase abundances (10% of sufficient vs. 50% of sufficient); however, hepatic mRNA for the carboxylases and for HCS did not change significantly in either dams or fetuses. These observations suggest that maternal biotin deficiency results in a lack of adequate biotin to biotinylate apocarboxylases in the fetus despite the normal expression of genes coding for the apocarboxylases and holocarboxylase synthetase.     

Biotin amplification of biotin and horseradish peroxidase signals in histochemical stains.

A procedure is described for intensifying histochemical reactions by amplification of biotinylated sites. This is achieved by deposition of biotinylated tyramine on the tissue through the enzymatic action of horseradish peroxidase (HRP). The amplified biotin sites are subsequently visualized by binding them to avidin, to which a marker is attached. This amplification greatly increases the sensitivity of staining procedures that employ HRP (and/or biotin) in tissue. For neuroanatomical pathway tracing methods, the procedure greatly increases the detectability of the injected tracer. For lectin histochemistry and immunohistochemistry, the amplification requires that the lectin or primary antibody be greatly diluted. This dilution results in less background staining and yet strong signals are produced even when very dilute reagents are used. Alternatively, the amplification permits much shorter incubations in primary antibodies when dilutions are used that would ordinarily be used with conventional bridge techniques. The procedure is also useful for amplifying very weak signals, such as those of immunoreactions in glutaraldehyde-fixed tissue. The amplification procedure, together with the availability of avidin probes labeled with fluorochromes, colloidal gold, or enzyme systems other than HRP, provides a means of greatly increasing the versatility of a variety of histochemical reactions, including those for detecting in situ hybridization probes, in addition to increasing the sensitivity of the reactions.     

Tribulus terrestris and female reproductive system health: A comprehensive review

BackgroundTribulus terrestris L. (T. terrestris) positive performance on the male sexual system has been confirmed, but little is known about its effects on the female reproductive system.PurposeThis review discussed in detail the beneficial impact of T. terrestris and its secondary metabolites on the female reproductive system.Study design and methodsIn this review, the scientific Databases of Science direct, Pubmed, Web of Science, Google, Google Scholar, Researchgate, EMBASE, Scientific Information (SID), and Elsevier were searched profoundly. Studies about the pharmacological activities of T. terrestris on the female reproductive system in each aspect of investigations: human, in vivo, and in vitro studies, in the period from 1998 to 2020 were admitted. Our study was not limited by the language of publications.Results23 articles about the effects of T. terrestris on the female reproductive system were found. These studies approved the T. terrestris efficacy on improvements in histological features of the ovary and uterus of polycystic ovary syndrome patients as well as the well-working of normal ovaries, enhancements in the sexual desire of postmenopausal syndrome, improve ovarian and breast cancers.ConclusionThese studies showed that the positive effect of T. terrestris on the female reproductive system was due to the presence of a secondary metabolite called protodioscin; a steroidal saponin compound, as the dominant active component of this plant.