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Biomedical subjects

W H B Wallace

Publications and source records attributed to W H B Wallace.

15 recordsLinked to original sources
PubMed2006

Undetectable salivary testosterone in young women with premature ovarian failure.

BACKGROUND: The extent of androgen deficiency in young women with premature ovarian failure (POF) is unclear. AIM: Cross-sectional study of androgen status in young women with POF. PATIENTS: Twenty women with POF: six had Turner syndrome (group A); eight had iatrogenic POF either secondary to bilateral oophorectomy or treatment of malignancy (group B); and six had idiopathic POF (group C). The median age was 30.5 years (range 19-39); in groups B and C the median duration of ovarian failure was 10.0 years (range 1-35). METHODS: After a 2-month wash-out period without sex steroid replacement (SSR), serum testosterone (T), androstenedione (A4), dehydroepiandrosterone (DHEAS), SHBG, salivary testosterone (SalT) and the free androgen index [FAI = (serum T/SHBG) x 100] were measured. RESULTS: Median serum A4 was 4.6 nmol/l (10th, 90th centiles, 3.6, 5.1) and DHEAS was 3.2 micromol/l (10th, 90th centiles, 2.3, 9.3). Although median serum T was relatively low at 1.4 nmol/l (10th, 90th centiles, 1.1, 1.7), median SHBG was also low at 34 nmol/l (10th, 90th centiles 22.2, 67.5) and the median calculated FAI was within the normal range at 3.7 (10th, 90th centiles, 2.3, 7.0). However, SalT was undetectable in almost all subjects in the three groups of POF. CONCLUSIONS: Serum T and SHBG are relatively low in young women with POF and their FAI is therefore within the normal range. However, SalT, which measures free testosterone, is consistently low to undetectable in these young women with POF. The reliability of the FAI as a marker of androgen deficiency remains questionable.

Adult↗
PubMed2005

A comparison of self-reported satisfaction between adolescents treated in a "teenage" unit with those treated in adult or paediatric units.

BACKGROUND: Despite recommendations that adolescents should have in-patient management amongst their peers, there is little literature to support this. The study aim was to evaluate and contrast patient satisfaction for teenage cancer patients treated in two settings. The first is a split site unit (a paediatric ward and adult cancer centre in different locations within one city) and the second, a dedicated adolescent unit for patients aged 13-20. PROCEDURE: Eligible patients aged 13-20 years received treatment from September 1997 to June 2000 and totalled sixty-five adolescents. The patients were identified at both centres from departmental databases. Postal questionnaires (the Youth Satisfaction Questionnaire) were sent to those eligible. RESULTS: Patients receiving treatment in the teenage cancer unit (TCU) were not significantly more satisfied overall than those receiving treatment in adult or paediatric units. However, significant differences were noted in: recreational and relaxation facilities (P < 0.005, P < 0.0002), studying space (P < 0.004), ward noise (P < 0.02), and company of the same age (P < 0.0001). The Grade Point Average (a score of all specific items) was higher in favour of the TCU (P < 0.03). Patients at both centres were dissatisfied with hospital food and menus offered. CONCLUSIONS: Adolescents with cancer are satisfied with the overall care they receive independent of whether it is a TCU or a split site unit. Teenagers are significantly more satisfied with environmental aspects of care in the TCU. More research is required to establish the correct provision for teenagers with cancer. This is the first study that contrasts satisfaction between different centres and thus adding to an understanding of the needs of teenagers with cancer.

Adolescent↗
PubMed2005

Subfertility in children and young people treated for solid and haematological malignancies.

Children treated for cancer may exhibit impaired fertility in later life. A number of chemotherapeutic agents have been identified as being gonadotoxic, and certain treatment regimens are particularly associated with subsequent infertility. Radiotherapy can also cause gonadal damage, most notably after direct testicular or pelvic irradiation or following total body irradiation. Because of the varied nature of the cytotoxic insult, it can be difficult to predict the likelihood of infertility in later life. Currently, cryopreservation of spermatozoa, oocytes or embryos is the only method of preserving fertility in patients receiving gonadotoxic therapy. This is only applicable to postpubertal patients and can be problematic in the adolescent age group. At present there is no provision for the prepubertal child, although there are a number of experimental methods being investigated. However, in addition to the many scientific and technical issues to be overcome before clinical application of such techniques, a number of ethical and legal issues must also be addressed to ensure a safe and realistic prospect for future fertility in these patients.

Adolescent↗
PubMed2004

Spontaneous conception in a young woman who had ovarian cortical tissue cryopreserved before chemotherapy and radiotherapy for a Ewing's sarcoma of the pelvis: case report.

We report the case of a 14 year old girl who presented with a non-metastatic Ewing's sarcoma involving her superior pubic ramus. She received 14 courses of alkylating agent-based chemotherapy and direct radiation to her hemi-pelvis (55 Gy) and is alive and disease-free 8 years later. Multiple biopsies of ovarian cortical tissue were cryopreserved, with her written consent, before treatment began. Ovarian failure was confirmed on completion of treatment with cessation of menses and persistently elevated serum gonadotrophin and low estradiol levels on repeated measurement over 2 years. HRT was initiated. Irregular vaginal bleeding occurred due to radiation vaginitis. Reimplantation of ovarian cortical tissue was considered at 19 years as fertility was desired, but the decision deferred. A spontaneous conception occurred 1 year later and a healthy boy (birthweight 2.9 kg, 3rd-10th centile) was delivered at term by elective Caesarean section. This is the first case of a spontaneous conception occurring in a young woman with documented ovarian failure in whom ovarian cortical tissue had been cryopreserved. Clinicians should be aware of the possibility of spontaneous conception despite confirmed ovarian failure in young women successfully treated for cancer.

Adolescent↗
PubMed2004

Effects of methotrexate on human bone cell responses to mechanical stimulation.

OBJECTIVES: Methotrexate (MTX), which is prescribed in the treatment of malignancy and autoimmune disease, has detrimental effects on a number of organ systems, including bone. At present, the exact mechanism of action of MTX on bone at the cellular level is unclear. Mechanical stimuli imparted by stretch, pressure, fluid flow and shear stress result in a variety of biochemical responses that are important in bone metabolism. Cyclical mechanical stimulation at 0.33 Hz induces rapid cell membrane hyperpolarization of human bone cells (HBC) via an integrin-mediated pathway which includes an IL-1beta autocrine/paracrine loop. This study was undertaken to investigate the effect of MTX on responses of HBC to 0.33 Hz mechanical stimulation. METHODS: Electrophysiological responses of HBC were measured before and after mechanical stimulation at 0.33 Hz in the presence or absence of MTX. Semiquantitative RT-PCR was used to investigate effects of MTX on relative levels of type-1 collagen and bone morphogenetic protein-4 (BMP-4) following 0.33 Hz mechanical stimulation. RESULTS: MTX dose-dependently inhibited HBC hyperpolarization in response to 0.33 Hz mechanical stimulation. Production/release of IL-1beta was inhibited by MTX, whereas its effects on target cells were not. Mechanical stimulation of HBC at 0.33 Hz caused a significant decrease in relative levels of BMP-4 mRNA, whereas relative levels of type-1 collagen mRNA were consistently increased, although these increases did not reach statistical significance. These trends were unaffected by MTX. CONCLUSIONS: These studies show that MTX affects HBC mechanotransduction by interfering with integrin-mediated signalling. The data also suggest that the mechanotransduction pathway responsible for the regulation of type-1 collagen and BMP-4 gene expression may be distinct from the IL-1beta-mediated signalling pathway.

Bone Morphogenetic Protein 4↗
PubMed2003

Is inhibin B a potential marker of gonadotoxicity in prepubertal children treated for cancer?

BACKGROUND AND OBJECTIVE: Chemotherapy treatment of childhood cancer may impair gonadal function, which may be manifested only in adulthood as permanent sterility. Detection of gonadal dysfunction in prepubertal children has been hampered by the absence of a sensitive marker. Inhibin B is secreted by small antral follicles and Sertoli cells in females and males, respectively, and may be a marker of gonadal function in prepubertal children. The aim of this pilot study was to evaluate inhibin B in relation to sensitive measurements of gonadotrophins as markers of the early gonadotoxic effects of chemotherapy in prepubertal children treated for cancer. STUDY DESIGN AND SUBJECTS: Twenty-five prepubertal children (9 females), median age 4.5 years (range 1.2-12.8 years) with cancer (16 solid tumours, nine acute lymphoblastic leukaemia, ALL) were studied longitudinally. Blood samples were collected before and during chemotherapy (solid tumours) or immediately following induction and first intensification (ALL). Post-treatment (1-6 months) samples were collected in 12 of the patients (5 females). MEASUREMENTS: Dimeric inhibin B was measured by double antibody enzyme-linked immunosorbent assay (ELISA). FSH and LH were measured by sensitive time-resolved immunofluorescence. RESULTS: Girls: Pretreatment inhibin B was slightly high in one girl but normal for age and sex in all others: median 16.1 (range 9.4-186.2) ng/l, median SD score +0.2 (-1.3 to +2.6). Inhibin B decreased to undetectable levels (< 8 ng/l) in 8/9 girls during treatment (P = 0.03), with no accompanying rise in FSH or LH. Post-treatment recovery of inhibin B was variable: median 16.1 (range < 8.0-44.2) ng/l, median SD score +0.1 (range < -2.4 to +1.8). Sustained undetectable inhibin B levels were observed in 2/5 girls with correspondingly elevated FSH concentrations (11.8 and 10.9 U/l). Boys: Inhibin B was normal for age and sex in all boys before treatment with no significant change during or after treatment (medians 93 ng/l, 85 ng/l and 94 ng/l, SD scores -0.3, -0.6 and -0.2, respectively). Inhibin B decreased to undetectable levels in one boy post-treatment with no accompanying increase in FSH or LH. CONCLUSIONS: In prepubertal girls with cancer, chemotherapy is associated with suppression of inhibin B, usually transient, which may indicate arrest of follicle development. Sustained suppression of inhibin B following treatment may be indicative of permanent ovarian damage. In prepubertal boys, chemotherapy had little immediate effect on Sertoli cell production of inhibin B, although one boy showed a delayed effect. Inhibin B, together with sensitive measurements of FSH, may be a potential marker of the gonadotoxic effects of chemotherapy in prepubertal children with cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

The radiosensitivity of the human oocyte.

BACKGROUND: We determined the best model available for natural follicle decline in healthy women and used this to calculate the radiosensitivity of the human oocyte. METHODS: Ovarian failure was diagnosed in six patients with a median age of 13.2 years (range 12.5-16.0) who were treated with total body irradiation (14.4 Gy) at 11.5 years of age (4.9-15.1). We previously estimated the dose of radiation required to destroy 50% of the oocytes (LD(50)) to be <4 Gy. This estimate is an oversimplification, because decay represents an instantaneous rate of temporal change based upon the remaining population pool, expressed as a differential equation: dy/dx = -y[0.0595 + 3716/(11780 + y)], with initial value y(0) = 701 200. RESULTS: Solving the differential equation, we have estimated the number of follicles left after irradiation given as sol(51 - s + r), where r equals age at treatment, s equals age at diagnosis of ovarian failure, and 51 years is the average age of menopause. The surviving fraction of oocytes as a percentage is 100 times this value divided by sol(r). The mean surviving fraction for the six cases is 0.66%. We obtain a function, g(z), which decreases in value from 100% at zero dosage to mean value at dosage z = 14.4 Gy. We have g(z) = 10(mx+c), where c = log(10)100 = 2, and m = [log(10)(0.66) - c]/14.4. Solving g(z) = 50 gives an LD(50) of 1.99. CONCLUSIONS: Based on new data and a revised mathematical model of natural oocyte decline, we have determined the surviving fraction of oocytes following irradiation and estimate the LD(50) of the human oocyte to be <2 Gy.

Adolescent↗
PubMed2003

Role of the neonatal period of pituitary-testicular activity in germ cell proliferation and differentiation in the primate testis.

BACKGROUND: The neonatal period of pituitary-testicular activity (NPTA) in human males has been hypothesized to play a role in germ cell proliferation and differentiation and to be defective in cryptorchid testes. The present study was carried out to establish in the marmoset if suppression of the NPTA, by treatment with a GnRH antagonist, results in impaired germ cell proliferation and/or differentiation. METHODS: Comparison of germ cell (GC) numbers and differentiation from gonocytes to pre-spermatogonia and spermatogonia, at birth (in controls) and at the end of the NPTA in marmoset co-twin males treated from birth to age 14 weeks with vehicle or GnRH antagonist. RESULTS: From birth to age 18-24 weeks, testis weight increased approximately 5-fold and GC number approximately 10-fold, including increased numbers of gonocytes and pre-spermatogonia and the first appearance of spermatogonia. Treatment with GnRH antagonist attenuated the increase in testis weight and GC numbers, but the effect was only partial (24-30% reduction), and the relative proportions of gonocytes, pre-spermatogonia and spermatogonia in the GnRH antagonist-treated group were unchanged from control values. CONCLUSIONS: The NPTA plays only a minor, if any, role in GC proliferation and differentiation in the marmoset. The changes in GnRH antagonist-treated co-twins may reflect impaired GC survival due to withdrawal of gonadotrophin support for Sertoli cells. These findings do not support a pivotal role for the NPTA in neonatal GC development in primates.

Animals↗
PubMed2003

Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Müllerian hormone, inhibin B and ovarian ultrasound.

BACKGROUND: Treatment of cancer during childhood may result in loss of primordial follicles from the ovary. METHODS: Ten cancer survivors and 11 controls with regular menstrual cycles, in addition to 10 cancer survivors and 10 controls taking the combined oral contraceptive pill (COCP) were recruited. Subjects were investigated on days 3-5 of a menstrual cycle, or week 3 of COCP administration before and 24 h after administration of 225 IU FSH. RESULTS: Serum FSH levels were elevated in cancer survivors with regular menstrual cycles (7.5 +/- 1.4 versus 4.2 +/- 0.3 IU/l; P = 0.02), while anti-Müllerian hormone (AMH) levels were lower (13.0 +/- 3.0 versus 21.0 +/- 3.4 pmol/l; P < 0.05). Other hormone levels were unchanged. Ovarian volume was smaller in cancer survivors than controls (3.0 +/- 0.5 versus 5.0 +/- 0.8 ml; P < 0.05), but antral follicle count (AFC) was similar. During COCP administration, inhibin B remained undetectable in six cancer survivors after FSH administration, whereas all controls showed a rise in inhibin B levels. The AFC was lower in cancer survivors than in controls (4.2 +/- 0.8 versus 7.2 +/- 0.8; P = 0.02). Ovarian volume was low in both groups, but did not differ between them. CONCLUSIONS: The study results demonstrate both hormonal and biophysical evidence of partial loss of the ovarian reserve in young cancer survivors. This was detected both in women with normal menstrual cycles and during COCP administration.

Adolescent↗
PubMed2003

Preservation of fertility in children treated for cancer.

As treatment for childhood cancer has become increasingly successful, adverse effects on reproductive function are assuming greater importance. Preservation of fertility before treatment must be considered in all young patients at high risk of infertility, and provision of such services requires collaboration between oncology centres and assisted conception units. The UK Children's Cancer Study Group is planning to audit current management of preservation of reproductive function in young patients with cancer, and the British Fertility Society is preparing a voluntary code of best practice to guide and inform clinicians and scientists. Limitation of radiation exposure by shielding of the testes and ovaries should be practiced where possible and sperm banking should be offered to all sexually mature boys at risk of infertility. The rapidly advancing experimental techniques for harvesting of gonadal tissue must be considered and embarked on without unrealistic expectations, although future utilisation of the tissue is unlikely to be realised until the next decade.

Antineoplastic Agents↗
PubMed2002

Treatment of paediatric Hodgkin's disease. a balance of risks.

Hodgkin's disease is one of the commoner malignancies presenting in adolescence and young adulthood and is curable in the majority of cases. A number of therapeutic regimens have been used successfully, often at the expense of the development of side-effects in later life, including second malignancies, infertility and cardiac disease. We discuss the challenge faced by paediatric oncologists today in finding the balance between maximising cure and minimising the late effects.

Adolescent↗
PubMed2002

Testicular changes during infantile 'quiescence' in the marmoset and their gonadotrophin dependence: a model for investigating susceptibility of the prepubertal human testis to cancer therapy?

BACKGROUND: Inexplicably, boys treated with some therapies for cancer at age 2-10 years, a time of supposed 'testicular quiescence', are at risk of low sperm counts/infertility in adulthood. Our aims were to use the marmoset as a surrogate for man to establish testicular cell function/activity during 'quiescence' between the neonatal period and puberty, and to test if any cell activity could be suppressed by prior treatment with a GnRH antagonist. METHODS AND RESULTS: Based on immunoexpression studies, functional development of Sertoli cells (SGP-2, androgen receptor) and Leydig cells (3 beta-hydroxysteroid dehydrogenase) was detectable at an age (35 weeks) when the testis is considered to be quiescent, and in advance of the pubertal rise in blood testosterone levels (50-60 weeks). Other changes at 35 weeks were the appearance of focal seminiferous tubule lumens and proliferating germ cells [indicated by immunoexpression of proliferating cell nuclear antigen (PCNA)]. Treatment from 25 to 35 weeks with GnRH antagonist largely (>85%) prevented these changes. However, the PCNA-labelling index of spermatogonia in GnRH antagonist-treated animals did not differ from controls (41.3 versus 43.6%) though total spermatogonia volume per testis was reduced by 41%. Some protein markers (inhibin-alpha, estrogen receptor-beta) showed little change with age or treatment. Beyond 35 weeks, GnRH antagonist-treated animals showed a delay in the pubertal rise in plasma testosterone levels. CONCLUSIONS: These findings reinforce the view that the 'childhood' testis is not quiescent. This may explain the damaging effects of some cancer therapies on subsequent fertility of boys and raises the issue of protective intervention. The present studies suggest that GnRH antagonist-based intervention might be only partially successful. Identification of the factors regulating spermatogonial development in the infant marmoset may aid in the design of such strategies.

Aging↗
PubMed2002

Investigation of suppression of the hypothalamic-pituitary-gonadal axis to restore spermatogenesis in azoospermic men treated for childhood cancer.

BACKGROUND: Does suppression of the hypothalamic-pituitary-gonadal (HPG) axis restore spermatogenesis in men rendered azoospermic following treatment of childhood cancer? METHODS: Seven men with azoospermia secondary to treatment for childhood cancer, median age (range), 22.2 (18-25.3) years, aged 10.4 (4.4-13.3) years at original diagnosis, participated. Each subject underwent semen analysis and testicular biopsy, followed by treatment with medroxyprogesterone acetate (MPA), 300 mg i.m. repeated after 12 weeks, with 800 mg testosterone pellets s.c. on day 1 to suppress the HPG axis. Hormone and semen analysis was performed every 6 weeks for 48 weeks. A second testicular biopsy was performed at week 48. RESULTS: Before HPG axis suppression, mean +/- SEM plasma LH was 9.0 +/- 1.8 U/l, testosterone 17.9 +/- 1.5 nmol/l and FSH 22.4 +/- 4.4 U/l. Median (range) venous plasma and seminal plasma inhibin B levels were 10.0 (7.8-35) and 11.2 (7.8-770) ng/l respectively. During HPG suppression, FSH and LH levels were undetectable for > or =12 weeks followed by a gradual return to pretreatment concentrations by 48 weeks. All men remained azoospermic at study completion and complete absence of germ cells on biopsies was demonstrated by immunocytochemistry for all specimens pre- and post-HPG axis suppression. CONCLUSIONS: HPG axis suppression with MPA-testosterone for > or =12 weeks did not restore spermatogenesis in azoospermic men treated with gonadotoxic radiotherapy and chemotherapy for childhood cancer.

Adolescent↗