Bone marrow transplantation restores follicular maturation and steroid hormones production in a mouse model for primary ovarian failure

Recent studies suggest that bone marrow stem cells (BMSCs) are promising grafts to treat a variety of diseases, including reproductive dysfunction. Primary ovarian failure is characterized by amenorrhea and infertility in a normal karyotype female, with an elevated serum level of follicle-stimulating hormone (FSH) and a decrease level of estrogen caused by a mutation in FSH receptor (FSHR) gene. Currently, there is no effective treatment for this condition. The phenotype of FSHR (-/-) mouse, FORKO (follitropin receptor knockout), is a suitable model to study ovarian failure in humans. Female FORKO mice have elevated FSH, decreased estrogen levels, are sterile because of the absence of folliculogenesis, and display thin uteri and small nonfunctional ovaries. In this study, we determined the effects of BMSC transplantation on reproductive physiology in this animal model. Twenty four hours post BMSC transplantation, treated animals showed detectable estroidogeneic changes in daily vaginal smear. Significant increase in total body weight and reproductive organs was observed in treated animals. Hemotoxylin and eosin (H&E) evaluation of the ovaries demonstrated significant increase in both the maturation and the total number of the follicles in treated animals. The FSH dropped to 40-50% and estrogen increased 4-5.5 times in the serum of treated animals compared to controls. The FSHR mRNA was detected in the ovaries of treated animals. Our results show that intravenously injected BMSCs were able to reach the ovaries of FORKO mice, differentiate and express FHSR gene, make FSHR responsive to FSH, resume estrogen hormone production, and restore folliculogenesis.     

Production and validation of a polyclonal serum against bovine FSH receptor

In ovarian granulosa cells, follicle-stimulating hormone (FSH) regulates the proliferation and differentiation events required for follicular growth and oocyte maturation. FSH actions are mediated exclusively through the FSH receptor (FSHR). In cattle, the FSHR gene expression pattern during folliculogenesis and the implications of this receptor in reproductive disorders have been extensively studied. However, the limited availability of specific antibodies against bovine FSHR has restricted FSHR protein analysis. In the present study, we developed an anti-FSHR polyclonal serum by using a 14-kDa peptide conjugated to maltose binding protein. The antiserum obtained was characterized by western blot of protein extracts from bovine follicles, BGC-1 cells and primary cultures of granulosa cells stimulated with testosterone. Also, the blocking effect of serum on estradiol secretion and cell viability after gonadotropin stimulus was characterized in a functional in vitro assay. A 76-kDa protein, consistent with the predicted molecular size of full-length FSHR, was detected in ovarian tissue. Besides, two immunoreactive bands of 60-kDa and 30-kDa (only in cultured cells) were detected. These bands would be related to some of the isoforms of the receptor. Therefore, immunohistochemical assays allowed detecting FSHR in the cytoplasm of granulosa cells and an increase in its expression as follicles progressed from primordial to large preantral follicles. These results suggest that the anti-FSHR serum here developed has good reactivity and specificity against the native FSHR. Therefore, this antiserum may serve as a valuable tool for future studies of the biological function of FSHR in physiological conditions as well as of the molecular mechanism and functional involvement of FSHR in reproductive disorders.     

Supplementation of maturation medium with CoQ10 enhances developmental competence of ovine oocytes through improvement of mitochondrial function

In vitro maturation (IVM) can impair the balance between antioxidant capacity and oxidative stress, and jeopardize embryo development by increasing oxidative stress, reducing energy metabolism, and causing improper meiotic segregation. Balancing the energy production and reduction of oxidative stress can be achieved by supplementation with coenzyme Q10 (CoQ10), an electron transporter in the mitochondrial inner membrane. To improve the in vitro production of ovine embryos, we studied the effect of CoQ10 supplementation during the maturation of sheep oocytes. A minimum of 100 cumulus‐oocyte complexes (COCs) were matured in the presence of 15, 30, or 50 μM CoQ10 in three to five replicates; next, in vitro fertilization and culture in a subset of oocytes were done. Our data revealed that compared to control oocytes or other concentrations of CoQ10, supplementation with 30 µM CoQ10 resulted in a significant increase in blastocyst formation and hatching rates, improved the distribution, relative mass and potential membrane of mitochondria, decreased the levels of reactive oxygen species and glutathione and lessened the percentage of oocytes with misaligned chromosomes after spindle assembly. The relative expression levels of apoptosis markers CASPASE3 and BAX were significantly reduced in CoQ10‐treated oocytes and cumulus cells whereas the relative expression level of GDF9, an oocyte‐specific growth factor, significantly increased. In conclusion, supplementation with CoQ10 improves the quality of COCs and the subsequent developmental competence of the embryo.     

Folliculogenesis is impaired and granulosa cell apoptosis is increased in leptin-deficient mice

Leptin purportedly plays an important role in pubertal development in a number of mammalian species. Adult leptin-deficient (ob/ob) female mice are infertile, but the mechanisms responsible for the reproductive failure have not been fully elucidated. The major objective of the current study was to assess the effects of a leptin deficiency on ovarian folliculogenesis and apoptosis. Beginning at 4 wk of age, control (n = 8) and ob/ob (n = 7) mice were weighed and examined daily for vaginal opening. After 3 wk the mice were killed, and the reproductive organs were weighed. Ovaries were paraffin-embedded for hematoxylin and eosin histology, TUNEL assay, and immunohistochemistry for Fas, Fas ligand (FasL), and proliferating cell nuclear antigen (PCNA). Vaginal opening was delayed, uteri were smaller, and the number of primordial follicles and total number of ovarian follicles were subnormal in ob/ob animals. Leptin-deficient animals also had a higher number of atretic follicles than controls. Granulosa cells (predominantly in preantral and early antral follicles) of ob/ob mice exhibited increased apoptotic activity as documented by TUNEL assay and elevated expression of the apoptotic markers Fas and FasL, compared with that in control animals. Ovarian expression of PCNA, a marker of DNA replication, repair, or both, did not differ between ob/ob and control mice. The data suggest that a leptin deficiency in mice is associated with impaired folliculogenesis, which results in increased follicular atresia. This impairment may be one of the causative components of infertility in leptin-deficient animals.     

Coenzyme Q and protein/lipid oxidation in a BSE-infected transgenic mouse model

Oxidative stress and antioxidants play an important role in neurodegenerative diseases. However, the exact participation of antioxidants in the evolution of prion diseases is still largely unknown. The aim of this study was to assess brain levels of coenzyme Q (CoQ), an endogenous lipophilic antioxidant, and the antioxidant/pro-oxidant status by determining oxidative damage to proteins and lipids after intracerebral bovine spongiform encephalopathy (BSE) infection of transgenic mice expressing bovine prion protein (PrP). Our results indicate that, whereas the ratio between the two CoQ homologues present in mice (CoQ(9) and CoQ(10)) is not altered by prion infection during the course of the disease, significant increases in total CoQ(9) and CoQ(10) were observed in BSE-infected mice 150 days after inoculation. This time point coincided with the first manifestation of PrP(Sc) deposition in nervous tissue. In addition, CoQ(9) and CoQ(10) levels, neuropathological alterations, and PrP(Sc) deposition in nervous tissues underwent further increases as the illness progressed. Lipid and protein oxidation were observed only at the final stage of the disease after clinical signs had appeared. These findings indicate upregulation of CoQ(9)- and CoQ(10)-dependent antioxidant systems in response to the increased oxidative stress induced by prion infection in nervous tissue. However, the induction of these endogenous antioxidant systems seems to be insufficient to prevent the development of the illness.     

Effect of coenzyme Q10 intake on endogenous coenzyme Q content, mitochondrial electron transport chain, antioxidative defenses, and life span of mice

The main purpose of this study was to determine whether intake of coenzyme Q10, which can potentially act as both an antioxidant and a prooxidant, has an impact on indicators of oxidative stress and the aging process. Mice were fed diets providing daily supplements of 0, 93, or 371 mg CoQ10 /kg body weight, starting at 3.5 months of age. Effects on mitochondrial superoxide generation, activities of oxidoreductases, protein oxidative damage, glutathione redox state, and life span of male mice were determined. Amounts of CoQ9 and CoQ10, measured after 3.5 or 17.5 months of intake, in homogenates and mitochondria of liver, heart, kidney, skeletal muscle, and brain increased with the dosage and duration of CoQ10 intake in all the tissues except brain. Activities of mitochondrial electron transport chain oxidoreductases, rates of mitochondrial O2-* generation, state 3 respiration, carbonyl content, glutathione redox state of tissues, and activities of superoxide dismutase, catalase, and glutathione peroxidase, determined at 19 or 25 months of age, were unaffected by CoQ10 administration. Life span studies, conducted on 50 mice in each group, showed that CoQ10 administration had no effect on mortality. Altogether, the results indicated that contrary to the historical view, supplemental intake of CoQ10 elevates the endogenous content of both CoQ9 and CoQ10, but has no discernable effect on the main antioxidant defenses or prooxidant generation in most tissues, and has no impact on the life span of mice.     

Evaluation of the neuroprotective effects of electromagnetic fields and coenzyme Q10 on hippocampal injury in mouse

Electromagnetic fields (EMFs) are reported to interfere with chemical reactions involving free radical production. Coenzyme Q₁₀ (CoQ10) is a strong antioxidant with some neuroprotective activities. The purpose of this study was to examine and compare the neuroprotective effects of EMF and CoQ10 in a mouse model of hippocampal injury. Hippocampal injury was induced in mature female mice (25–30 g), using an intraperitoneal injection of trimethyltin hydroxide (TMT; 2.5 mg/kg). The experimental groups were exposed to EMF at a frequency of 50 Hz and intensity of 5.9 mT for 7 hr daily over 1 week or treated with CoQ10 (10 mg/kg) for 2 weeks following TMT injection. A Morris water maze apparatus was used to assess learning and spatial memory. Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) tests were also performed for the histopathological analysis of the hippocampus. Antiapoptotic genes were studied, using the Western blot technique. The water maze test showed memory improvement following treatment with CoQ10 and coadministration of CoQ10 + EMF. The Nissl staining and TUNEL tests indicated a decline in necrotic and apoptotic cell count following treatment with CoQ10 and coadministration of CoQ10 + EMF. The Western blot study indicated the upregulation of antiapoptotic genes in treatment with CoQ10, as well as coadministration. Also, treatment with EMF had no significant effects on reducing damage induced by TMT in the hippocampus. According to the results, EMF had no significant neuroprotective effects in comparison with CoQ10 on hippocampal injury in mice. Nevertheless, coadministration of EMF and CoQ10 could improve the neuroprotective effects of CoQ10.     

Absence of mutations in the coding regions of follicle-stimulating hormone receptor gene in Singapore Chinese women with premature ovarian failure and polycystic ovary syndrome.

Normal gonadal function is critically dependent on the integrity of pituitary-gonadal axis, where follicle-stimulating hormone (FSH) plays a key role. In the female, FSH is required for follicular growth, estrogen production and oocyte maturation. Its function is mediated by its specific receptor (FSHR), and defective FSHR has been shown to affect folliculogenesis and ovarian function. In this study, we screened the entire coding region of FSHR gene for pathogenic mutations in women with premature ovarian failure (POF) (n = 16) and polycystic ovary syndrome (PCOS) (n = 124) and found no mutations in these patients. Two known polymorphisms, Thr307Ala and Ser680Asn showed similar distributions of the allelic variations and protein isoforms in PCOS and normal control subjects (n = 236). It appears from this study that mutations in the coding regions of FSHR gene are not a causative factor of the above clinical manifestations in Chinese Singapore women.     

COENZYME Q10 TREATMENTS INFLUENCE THE LIFESPAN AND KEY BIOCHEMICAL RESISTANCE SYSTEMS IN THE HONEYBEE,Apis mellifera

Natural bioactive preparations that will boost apian resistance, aid body detoxification, or fight crucial bee diseases are in demand. Therefore, we examined the influence of coenzyme Q10 (CoQ10, 2,3‐dimethoxy, 5‐methyl, 6‐decaprenyl benzoquinone) treatment on honeybee lifespan, Nosema resistance, the activity/concentration of antioxidants, proteases and protease inhibitors, and biomarkers. CoQ10 slows age‐related metabolic processes. Workers that consumed CoQ10 lived longer than untreated controls and were less infested with Nosema spp. Relative to controls, the CoQ10‐treated workers had higher protein concentrations that increased with age but then they decreased in older bees. CoQ10 treatments increased the activities of antioxidant enzymes (superoxide dismutase, GPx, catalase, glutathione S‐transferase), protease inhibitors, biomarkers (aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase), the total antioxidant potential level, and concentrations of uric acid and creatinine. The activities of acidic, neutral, and alkaline proteases, and concentrations of albumin and urea were lower in the bees that were administered CoQ10. CoQ10 could be taken into consideration as a natural diet supplement in early spring before pollen sources become available in the temperate Central European climate. A response to CoQ10 administration that is similar to mammals supports our view that Apis mellifera is a model organism for biochemical gerontology.     

Micronutrient special issue: Coenzyme Q(10) requirements for DNA damage prevention

Coenzyme Q(10) (CoQ(10)) is an essential component for electron transport in the mitochondrial respiratory chain and serves as cofactor in several biological processes. The reduced form of CoQ(10) (ubiquinol, Q(10)H(2)) is an effective antioxidant in biological membranes. During the last years, particular interest has been grown on molecular effects of CoQ(10) supplementation on mechanisms related to DNA damage prevention. This review describes recent advances in our understanding about the impact of CoQ(10) on genomic stability in cells, animals and humans. With regard to several in vitro and in vivo studies, CoQ(10) provides protective effects on several markers of oxidative DNA damage and genomic stability. In comparison to the number of studies reporting preventive effects of CoQ(10) on oxidative stress biomarkers, CoQ(10) intervention studies in humans with a direct focus on markers of DNA damage are limited. Thus, more well-designed studies in healthy and disease populations with long-term follow up results are needed to substantiate the reported beneficial effects of CoQ(10) on prevention of DNA damage.     

Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging

Female reproductive capacity declines dramatically in the fourth decade of life as a result of an age‐related decrease in oocyte quality and quantity. The primary causes of reproductive aging and the molecular factors responsible for decreased oocyte quality remain elusive. Here, we show that aging of the female germ line is accompanied by mitochondrial dysfunction associated with decreased oxidative phosphorylation and reduced Adenosine tri‐phosphate (ATP) level. Diminished expression of the enzymes responsible for CoQ production, Pdss2 and Coq6, was observed in oocytes of older females in both mouse and human. The age‐related decline in oocyte quality and quantity could be reversed by the administration of CoQ10. Oocyte‐specific disruption of Pdss2 recapitulated many of the mitochondrial and reproductive phenotypes observed in the old females including reduced ATP production and increased meiotic spindle abnormalities, resulting in infertility. Ovarian reserve in the oocyte‐specific Pdss2‐deficient animals was diminished, leading to premature ovarian failure which could be prevented by maternal dietary administration of CoQ10. We conclude that impaired mitochondrial performance created by suboptimal CoQ10 availability can drive age‐associated oocyte deficits causing infertility.     

Development of antral follicles in cryopreserved cat ovarian tissue transplanted to immunodeficient mice

Ovarian cortex cryopreservation and xenotransplantation into immunodeficient mice represents a potential means for female germplasm conservation and an immediate model for investigation of folliculogenesis. The objectives of this study were to: (1) assess follicle survival after cryopreservation and transplantation of cat ovarian tissue into non-obese diabetic severely combined immunodeficient (NOD SCID) mice; and (2) evaluate the effects of gonadotropin treatments on follicular development in the transplanted tissue. Slices from the cat ovarian cortex were frozen and after thawing, transplanted under each kidney capsule of castrated male NOD SCID mice (eight xenografts in four mice). Sixty-two days after surgery, mice were randomly assigned (two per group) to gonadotropin-treated (eCG and hCG 88 h later) or control (saline-treated) groups. Twenty-four hours after the last injection, ovarian tissue was recovered and processed for histology. Fresh ovarian tissue from the same original source was similarly processed. Follicles were counted, measured, and classified as primordial, primary, secondary, or antral. Immunoreactive proliferating cell nuclear antigen (PCNA) stain was used to assess follicle viability. Microscopic examination revealed no evidence of necrosis or fibrosis. The grafts were well-vascularized, with follicles at all stages of development. Numbers of follicles in the transplanted tissue were markedly reduced compared to fresh tissue, with approximately 10% of follicles surviving freezing and transplantation procedures. Growing follicles positive for PCNA were found in all xenografts. Gonadotropin treatment did not alter the proportion of resting to growing follicles or mean follicle diameter by comparison with controls from untreated mice. By contrast, luteinization, but not ovulation, of antral follicles was observed only in grafts from treated mice. In summary, frozen-thawed cat ovarian cortex tissue not only survived xenotransplantation, it also contained follicles able to grow to antral stages. Exogenous gonadotropin treatment in this model resulted in luteinization of antral follicles but enhancement of follicular growth and ovulation did not occur.     

Life-long supplementation with a low dosage of coenzyme Q10 in the rat: effects on antioxidant status and DNA damage

Life-long low-dosage supplementation of coenzyme Q(10) (CoQ(10)) is studied in relation to the antioxidant status and DNA damage. Thirty-two male rats were assigned into two experimental groups differing in the supplementation or not with 0.7 mg/kg/day of CoQ(10). Eight rats per group were killed at 6 and 24 months. Plasma retinol, alpha-tocopherol, coenzyme Q, total antioxidant capacity and fatty acids were analysed. DNA strand breaks were studied in peripheral blood lymphocytes. Aging and supplementation led to significantly higher values for CoQ homologues, retinol and alpha-tocopherol. No difference in total antioxidant capacity was detected at 6 months but significantly lower values were found in aged control animals. Similar DNA strand breaks levels were found at 6 months. Aging led to significantly higher DNA strand breaks levels in both groups but animals supplemented with CoQ(10) led to a significantly lower increase in that marker. Aged rats showed significantly higher polyunsaturated fatty acids. This study demonstrates that lifelong intake of a low dosage of CoQ(10) enhances plasma levels of CoQ(9), CoQ(10), alpha-tocopherol and retinol. In addition, CoQ(10) supplementation attenuates the age-related fall in total antioxidant capacity of plasma and the increase in DNA damage in peripheral blood lymphocytes.     

Kisspeptin as autocrine/paracrine regulator of human ovarian cell functions: Possible interrelationships with FSH and its receptor

The present study aims to examine the role of kisspeptin (KP), FSH, and its receptor (FSHR), and their interrelationships in the control of basic human ovarian granulosa cells functions. We investigated: (1) the ability of granulosa cells to produce KP and FSHR, (2) the role of KP in the control of ovarian functions, and (3) the ability of KP to affect FSHR and to modify the FSH action on ovarian functions. The effects of KP alone (0, 10 and 100 ng/mL); or of KP (10 and 100 ng/mL) in combination with FSH (10 ng/mL) on cultured human granulosa cells were assessed. Viability, markers of proliferation (PCNA and cyclin B1) and apoptosis (bax and caspase 3), as well as accumulation of KP, FSHR, and steroid hormones, IGF-I, oxytocin (OT), and prostaglandin E2 (PGE2) release were analyzed by the Trypan blue exclusion test, quantitative immunocytochemistry, and ELISA. KP given at a low dose (10 ng/mL) stimulated viability, proliferation, inhibited apoptosis, promoted the release of progesterone (P4), estradiol (E2), IGF-I, OT, and PGE2, the accumulation of FSHR, but not testosterone (T) release. KP given at a high dose (100 ng/mL) had the opposite, inhibitory effect. FSH stimulated cell viability, proliferation and inhibited apoptosis, promoted P4, T, E2, IGF-I, and OT, but not PGE2 release. Furthermore, KP at a low dose promoted the stimulatory effect of FSH on viability, proliferation, P4, E2, and OT release, promoted its inhibitory action on apoptosis, but did not modify its action on T, IGF-I, and PGE2 output. KP at a high dose prevented and inverted FSH action. These results suggest an intra-ovarian production and a functional interrelationship between KP and FSH/FSHR in direct regulation of basic ovarian cell functions (viability, proliferation, apoptosis, and hormones release). The capability of KP to stimulate FSHR, the ability of FSH to promote ovarian functions, as well as the similarity of KP (10 ng/mL) and FSH action on granulosa cells’ viability, proliferation, apoptosis, steroid hormones, IGF-I, OT, and PGE2 release, suggest that FSH influence these cells could be mediated by KP. Moreover, the capability of KP (100 ng/mL) to decrease FSHR accumulation, basal and FSH-induced ovarian parameters, suggest that KP can suppress some ovarian granulosa cell functions via down-regulation of FSHR. These observations propose the existence of the FSH-KP axis up-regulating human ovarian cell functions.     

Mitochondrial dysfunction and Down's syndrome: is there a role for coenzyme Q(10) ?

Structural changes and abnormal function of mitochondria have been documented in Down's syndrome (DS) cells, patients, and animal models. DS cells in culture exhibit a wide array of functional mitochondrial abnormalities including reduced mitochondrial membrane potential, reduced ATP production, and decreased oxido-reductase activity. New research has also brought to central stage the prominent role of oxidative stress in this condition. This review focuses on recent advances in the field with a particular emphasis on novel translational approaches involving the utilization of coenzyme Q(10) (CoQ(10) ) to treat a variety of clinical phenotypes associated with DS that are linked to increased oxidative stress and energy deficits. CoQ(10) has already provided promising results in several different conditions associated with altered energy metabolism and oxidative stress in the CNS. Two studies conducted in Ancona investigated the effect of CoQ(10) treatment on DNA damage in DS patients. Although the effect of CoQ(10) was evidenced only at single cell level, the treatment affected the distribution of cells according to their content in oxidized bases. In fact, it produced a strong negative correlation linking cellular CoQ(10) content and the amount of oxidized purines. Results suggest that the effect of CoQ(10) treatment in DS not only reflects antioxidant efficacy, but likely modulates DNA repair mechanisms.     

Epigallocatechin gallate and theaflavins independently alleviate cyclophosphamide-induced ovarian damage by inhibiting the overactivation of primordial follicles and follicular atresia

BackgroundCyclophosphamide (CTX), which has been used to treat common female cancers for several years, often causes ovarian damage, early menopause and infertility. However, strategies for the effective prevention and treatment of CTX-induced ovarian damage are still lacking. Epigallocatechin gallate (EGCG) and theaflavins (TFs), key molecules derived from green tea or black tea, have been shown to exert preventive effects on many ageing-related diseases.PurposeWe aimed to explore the potential preventive and protective effects of EGCG and TFs on CTX-induced ovarian damage and compare the two compounds.Study DesignSix-week-old female mice were administered a low or high dose of EGCG or TFs. The low dose was equivalent to the average daily amount of tea consumed by a drinker.MethodsWe determined the oestrous cycle and serum hormone levels to evaluate ovarian endocrine function, and we performed mating tests for reproductivity. We also assessed the follicle count and AMH level to evaluate ovarian reserve, and we performed Masson's trichrome and Sirius red staining to evaluate ovarian fibrosis. We conducted γ-H2AX and TUNEL analyses to evaluate DNA damage, and we also measured the relevant indicators of oxidative stress and follicular activation, including NRF2, HO-1, SOD2, AKT, mTOR and RPS6.ResultsEGCG and TFs treatment independently improved the ovarian endocrine function and reproductivity of mice that were administered CTX. EGCG and TFs also increased the ovarian reserve of these animals. Furthermore, EGCG and TFs alleviated oxidation-induced damage to ovarian DNA in mice by activating the NRF2/HO-1 and SOD2 pathways and reducing the apoptosis of growing follicles. At the same time, EGCG and TFs reduced the overactivation of primordial follicles by inhibiting the AKT/mTOR/RPS6 pathway.ConclusionThe present study showed that EGCG and TFs independently improved ovarian function in mice with CTX-induced ovarian damage, thereby providing useful information for designing a potential clinical strategy that will protect against chemotherapy-induced ovarian damage.     

Coenzyme Q10 concentration in the plasma of children suffering from acute lymphoblastic leukaemia before and during induction treatment

Coenzyme Q10 (CoQ10) is used by the body as an endogenous antioxidant. This property combined with its essential function in mitochondrial energy production suggests that it may have therapeutic potential in cancer treatment. As part of the body's antioxidant defence against free radical production, CoQ10 concentrations may change during anti-cancer chemotherapy. Our study measured CoQ10 concentration in the plasma of 27 children with acute lymphoblastic leukaemia (ALL) at the time of diagnosis, during induction (protocol ALL-BFM 2000), and post induction treatment. The starting values were compared to the CoQ10 concentrations in 92 healthy children. The total CoQ10 concentration and its redox status were measured by HPLC using electrochemical detection and internal standardisation. While the CoQ10 concentration in the plasma of children with ALL was within a normal range at the time of diagnosis (0.99 +/- 0.41 pmol/microl), a drastic increase was observed during induction treatment (2.19 +/- 1.01 pmol/mul on day 33). This increase was accompanied by shift in the redox status in favour of the reduced form of CoQ10. The increase in CoQ10 concentration during induction treatment may be attributed to the activation of a natural antioxidative defence mechanism, endocrine influence on CoQ10 synthesis from steroid treatment, or a shift in CoQ10 from the damaged cells to the plasma after cell lysis.     

The Parkes lecture: controlled ovarian stimulation in women

Recent advances in knowledge of the endocrine and paracrine mechanisms that regulate human ovarian folliculogenesis have been parallelled by the introduction into clinical practice of new drugs that can be used safely and effectively to stimulate ovarian function in infertile women. Most notably, recombinant DNA technology has been applied to the production of molecularly pure forms of the gonadotrophins, FSH and LH, opening the way to the development of improved strategies for manipulating the ovarian paracrine system. The clinical objectives of controlled ovarian stimulation fall into two categories, depending on patient needs: (1) induction of multiple follicles from which mature oocytes can be harvested for use in assisted reproduction protocols such as in vitro fertilization and embryo transfer; or (2) induction of spontaneous ovulation of a single mature follicle so that conception might occur in vivo. This review summarizes the physiological principles upon which the use of gonadotrophins for clinical purposes is based, highlighting new opportunities for improved treatment as a result of the availability of recombinant FSH and LH.