C.C.M. Beerendonk

Anti-Müllerian Hormone, Inhibin B, and Antral Follicle Count in Young Women with Ovarian Failure

CONTEXT Ovarian dysfunction is classically categorized on the basis of cycle history, FSH, and estradiol levels. Novel ovarian markers may provide a more direct insight into follicular quantity in hypergonadotropic women. OBJECTIVE The objective of the study was to investigate the distribution of novel ovarian markers in young hypergonadotropic women as compared with normogonadotropic regularly menstruating women. DESIGN This was a nationwide prospective cohort study. SETTING The study was conducted at 10 hospitals in The Netherlands. PATIENTS Women below age 40 yr with regular menses and normal FSH (controls; n = 83), regular menstrual cycles and elevated FSH [incipient ovarian failure (IOF); n = 68]; oligomenorrhea and elevated FSH [referred to as transitional ovarian failure (TOF); n = 79]; or at least 4 months amenorrhea together with FSH levels exceeding 40 IU/liter [premature ovarian failure (POF); n = 112]. MAIN OUTCOME MEASURES Serum levels of anti-Müllerian hormone (AMH), inhibin B, and antral follicle count (AFC) was measured. RESULTS All POF patients showed AMH levels below the fifth percentile (p(5)) of normoovulatory women. Normal AMH levels (>p(5)) could be identified in 75% of IOF, 33% of TOF patients, and 98% of controls. AFC and AMH levels changed with increasing age (P < 0.0001), whereas inhibin B did not (P = 0.26). AMH levels were significantly different between TOF and IOF over the entire age range, whereas AFC became similar for TOF and IOF at higher ages. CONCLUSIONS Compared with inhibin B and AFC, AMH was more consistently correlated with the clinical degree of follicle pool depletion in young women presenting with elevated FSH levels. AMH may provide a more accurate assessment of the follicle pool in young hypergonadotropic patients, especially in the clinically challenging subgroups of patients with elevated FSH and regular menses (i.e. IOF) and in hypergonadotropic women with cycle disturbances not fulfilling the POF diagnostic criteria (i.e. TOF).

Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review

BACKGROUND The risk of recurrent oncological disease due to the reintroduction of cancer cells via autotransplantation of cryopreserved ovarian tissue is unknown. METHODS A systematic review of literature derived from MEDLINE, EMBASE and the Cochrane Library was conducted. Studies on follow-up after autotransplantation; detection of cancer cells in ovarian tissue from oncological patients by histology, polymerase chain reaction or xenotransplantation; and epidemiological data on ovarian metastases were included. RESULTS A total of 289 studies were included. Metastases were repeatedly detected in ovarian tissue obtained for cryopreservation purposes from patients with leukaemia, as well as in one patient with Ewing sarcoma. No metastases were detected in ovarian tissue from lymphoma and breast cancer patients who had their ovarian tissue cryopreserved. Clinical studies indicated that one should be concerned about autotransplantation safety in patients with colorectal, gastric and endometrial cancer. For patients with low-stage cervical carcinoma, clinical data were relatively reassuring, but studies focused on the detection of metastases were scarce. Oncological recurrence has been described in one survivor of cervical cancer and one survivor of breast cancer who had their ovarian tissue autotransplanted, although these recurrences may not be related to the transplantation. CONCLUSIONS It is advisable to refrain from ovarian tissue autotransplantation in survivors of leukaemia. With survivors of all other malignancies, current knowledge regarding the safety of autotransplantation should be discussed. The most reassuring data regarding autotransplantation safety were found for lymphoma patients.

OVARIAN HYPERSTIMULATION SYNDROME : FACTS AND FALLACIES

Severe or critical ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian hyperstimulation for assisted reproduction techniques (ART). The syndrome is characterized by cystic enlargement of the ovaries and fluid shifts from the intravascular to the third space. The morbidity in OHSS is mainly determined by the hemodynamic changes caused by increased capillary permeability. The incidence of OHSS depends on definitions, risk factors, ovarian stimulation protocols, luteal support and conception. Currently, research on the pathogenesis of OHSS is focused on increased capillary permeability. Several theories are reviewed. Until the pathogenesis of OHSS becomes clear, treatment is restricted to supportive therapy. The various proposals for management of OHSS are discussed and, based on the available data, directions for the management of various grades of OHSS are summarized. However, prevention and early recognition are still the most important tools to handle OHSS. A flowchart with preventive measures for OHSS is presented derived from the available literature.

Standardized Multidisciplinary Evaluation Yields Significant Previously Undiagnosed Morbidity in Adult Women with Turner Syndrome

CONTEXT Besides short stature and gonadal dysgenesis, Turner syndrome (TS) is associated with various abnormalities. Adults with TS have a reduced life expectancy, mainly related to structural abnormalities of the heart and aorta, and an increased risk of atherosclerosis. OBJECTIVE Our objective was to investigate the yield of an initial standardized multidisciplinary screening in adult TS patients. DESIGN AND SETTING This was an observational study at a multidisciplinary care unit for adult women with TS. PARTICIPANTS Participants were adult women with TS (n = 150). Mean age was 31.0 ± 10.4 yr, with 47% karyotype 45,X. INTERVENTIONS All women were consulted by an endocrinologist, a gynecologist, a cardiologist, an otorhinolaryngologist, and when indicated, a psychologist. The screening included magnetic resonance imaging of the heart and aorta, echocardiography, electrocardiogram, dual-energy x-ray absorptiometry, renal ultrasound, audiogram, and laboratory investigations according to international expert recommendations. MAIN OUTCOME MEASURES New diagnoses and prevalence of TS-associated morbidity were evaluated. RESULTS Thirty percent of patients currently lacked medical follow-up, and 15% lacked estrogen replacement therapy in the recent last years. The following disorders were newly diagnosed: bicuspid aortic valve (n = 13), coarctation of the aorta (n = 9), elongation of the transverse aortic arch (n = 27), dilation of the aorta (n = 34), osteoporosis (n = 8), osteopenia (n = 56), renal abnormalities (n = 7), subclinical hypothyroidism (n = 33), celiac disease (n = 3), glucose intolerance (n = 12), dyslipidemia (n = 52), hypertension (n = 39), and hearing loss warranting a hearing aid (n = 8). Psychological consultation was needed in 23 cases. CONCLUSIONS Standardized multidisciplinary evaluation of adult women with TS as advocated by expert opinion is effective and identifies significant morbidity. Girls with TS benefit from a careful transition to ongoing adult medical care.

Severity of Virilization Is Associated with Cosmetic Appearance and Sexual Function in Women with Congenital Adrenal Hyperplasia: A Cross-Sectional Study

INTRODUCTION Women with the classical form of congenital adrenal hyperplasia (CAH) are born with different degrees of virilization of the external genitalia. Feminizing surgery is often performed in childhood to change the appearance of the genitalia and to enable penile-vaginal intercourse later in life. There are suggestions that this affects sexual functioning. AIMS The aim is to study the anatomical, surgical, cosmetic, and psychosexual outcomes in women with CAH. METHODS Forty women with CAH, aged over 15 years, from two referral centers for management of Disorders of Sex Development in the Netherlands were included. Physical and functional status were assessed by a gynecological interview and examination. Sexual functioning was assessed with the Female Sexual Function Index and Female Sexual Distress Scale-Revised scales and compared with a reference group. MEAN OUTCOME MEASURES Surgery performed, anatomy, cosmetic score, sexual function and distress. RESULTS Thirty-six of the 40 women had undergone feminizing surgery; 25 women (69%) underwent more than one operation. Resurgery was performed in seven of the 13 (54%) women who had had a single-stage procedure. Anatomical assessment showed reasonable outcomes. Multiple linear regression showed that only level of confluence had a significant effect on cosmetic outcome, the impact depending on the number of surgeries performed. Cosmetic evaluations did not differ between the women and the gynecologists. Only 20 women had experience of intercourse. Eight women reported dyspareunia; seven women reported urinary incontinence. The womens perceived sexual functioning was less satisfactory than in the reference group, and they reported more sexual distress. CONCLUSION The level of confluence was the major determinant for cosmetic outcome; the impact depended on the number of surgeries performed. Fifty-four percent of the women required resurgery after a single-stage procedure in childhood. Anatomical assessment showed reasonable outcomes. The women evaluated their sexual functioning and functional outcome less favorable than the reference group, and they experienced less often sexual intercourse.

Long-term psychosexual and anatomical outcome after vaginal dilation or vaginoplasty: a comparative study.

INTRODUCTION In patients with disorders of sex development requiring creation of a neovagina, a number of techniques are available, including surgical vaginoplasty and self-dilation therapy. Vaginal dilation therapy has been recommended as a first-line treatment because of its less invasive character and high success rate. However, no data exist on long-term psychosexual functioning after vaginal dilation as compared with that after vaginal surgery. AIMS The aim of this study is to compare the psychosexual and anatomical outcome of women with congenital vaginal hypoplasia followed in the same clinical setting after vaginoplasty with that after vaginal dilation. METHODS The sexual quality of life of 35 women at least 2 years after vaginoplasty (N = 15), vaginal dilation therapy (N = 8), or coital dilation/no treatment (N = 12) was investigated and compared with the Dutch test validation population (as control). MAIN OUTCOME MEASURES Psychosexual functioning was assessed with the female sexual Function index, the female sexual distress scale-revised, and a semi-structured interview. A gynecological examination was performed to determine the anatomical outcome after both vaginal treatment regimens. RESULTS After either treatment, 26% of these women had a shortened vaginal length of less than 6.6 cm, i.e., more than two standard deviations below the published mean value (9.6 ± 1.5 cm). Irrespective of the treatment, 47% of the patients had (a) sexual dysfunction(s) and experienced sexual distress. However, after vaginoplasty, patients reported significantly more problems with lubrication (P = 0.025) than after self-dilation therapy. CONCLUSION Both psychological and physical factors are predisposing for sexual difficulties. To optimize psychosexual comfort, the clinical management of women with vaginal hypoplasia needs to be multidisciplinary and individually tailored. With high success rates reported, vaginal dilation should remain the cornerstone of treatment.

Reproductive status in adult male long-term survivors of childhood cancer

BACKGROUND This study assessed the long-term effects of cancer therapies on reproductive status in adult male childhood cancer survivors, evaluated the treatment-related risk factors for hypergonadotropic hypogonadism and assessed the association between the FSH levels and the later need for assisted reproductive techniques (ART). METHODS The study cohort included adult male 5-year survivors of childhood cancer who were treated in our institution between 1966 and 2003. Data concerning patient and treatment characteristics, FSH, LH and testosterone levels and pregnancy outcome were collected. Multivariate regression analyses were performed to evaluate the treatment-related risk factors for disturbances in reproductive endocrine status. The diagnostic and predictive values of FSH and later need for ART were evaluated. RESULTS Data on reproductive endocrine status were available for 488 survivors (86.4%) of the 565 male survivors who visited the outpatient clinic in adulthood. The median follow-up time from initiation of treatment to first visit to the outpatient clinic in adulthood was 15 years. The prevalence rates of elevated FSH levels and decreased testosterone levels were 33 and 12%, respectively. The use of procarbazine, cyclophosphamide, vinca-alkaloids, other alkylating agents, pelvic/abdominal irradiation, total body irradiation and testicular surgery were identified as treatment-related risk factors for elevated FSH levels. During the follow-up period, 73 men reported 120 conceptions, which resulted in 103 live births. Of these men, 56 (77%) were able to achieve conception naturally. All men whose partners conceived by assisted reproductive techniques (n = 13) had elevated FSH levels at their first visit after their 18th birthday (sensitivity: 100%; 95% CI: 71-100%) and all male survivors with a normal FSH level did not need assisted reproductive techniques (negative predictive value: 100%; 95% CI: 89-100%). CONCLUSIONS One-third of young adult male survivors of childhood cancer has elevated FSH levels. FSH appears to be a very sensitive marker for the need of assisted reproductive techniques in male childhood cancer survivors.

Buccal cell FISH and blood PCR-Y detect high rates of X chromosomal mosaicism and Y chromosomal derivatives in patients with Turner syndrome

Turner syndrome (TS) is the result of (partial) X chromosome monosomy. In general, the diagnosis is based on karyotyping of 30 blood lymphocytes. This technique, however, does not rule out tissue mosaicism or low grade mosaicism in the blood. Because of the associated risk of gonadoblastoma, mosaicism is especially important in case this involves a Y chromosome. We investigated different approaches to improve the detection of mosaicisms in 162 adult women with TS (mean age 29.9 ± 10.3). Standard karyotyping identified 75 patients (46.3%) with a non-mosaic monosomy 45,X. Of these 75 patients, 63 underwent additional investigations including FISH on buccal cells with X- and Y-specific probes and PCR-Y on blood. FISH analysis of buccal cells revealed a mosaicism in 19 of the 63 patients (30.2%). In five patients the additional cell lines contained a (derivative) Y chromosome. With sensitive real-time PCR we confirmed the presence of this Y chromosome in blood in three of the five cases. Although Y chromosome material was established in ovarian tissue in two patients, no gonadoblastoma was found. Our results confirm the notion that TS patients with 45,X on conventional karyotyping often have tissue specific mosaicisms, some of which include a Y chromosome. Although further investigations are needed to estimate the risk of gonadoblastoma in patients with Y chromosome material in buccal cells, we conclude that FISH or real-time PCR on buccal cells should be considered in TS patients with 45,X on standard karyotyping.

Do Surgical Interventions Influence Psychosexual and Cosmetic Outcomes in Women with Disorders of Sex Development

Clinical practice developed to promote psychosexual well-being in DSD is under scrutiny. Although techniques for genital surgery have much improved lately, long-term studies on psychosexual functioning and cosmetic outcome on which to base treatment and counseling are scarce. We studied 91 women with a DSD. Feminizing surgery was performed in 64% of the women; in 60% of them, resurgery in puberty was needed after a single-stage procedure. Both patients and gynecologists were satisfied with the cosmetic appearance of the genitalia. However, forty percent of these females experienced sexuality-related distress and 66% was at risk for developing a sexual dysfunction, whether they had surgery or not. Recognizing the difficulty of accurate assessment, our data indicate that feminizing surgery does not seem to improve nor hamper psychosexual outcome, especially in patients with severe virilization.

Glucose/lactate metabolism of cryopreserved intact bovine ovaries as a novel quantitative marker to assess tissue cryodamage

For some patients, the autotransplantation of a cryopreserved-thawed intact ovary might be the best option to preserve their reproductive potential after fertility-threatening treatment. The best procedure to successfully cryopreserve a human ovary without inflicting a devastating level of cryodamage is to date unknown. To optimize this procedure, this study developed an assay to monitor the extent of cryodamage inflicted on bovine ovarian tissue by different cryopreservation protocols. The assay measures glucose and lactate metabolism of ovarian tissue fragments in vitro and determines the extent of cryodamage in cryopreserved ovaries. This study tested the cryoprotective effect of two different routes of administration of the cryoprotectant dimethylsulphoxide (DMSO). The cryoprotective effect was assessed in different tissue layers of the ovary, namely the cortex, the subcortex and the medulla. Submersion of intact ovaries in DMSO prior to freezing-thawing resulted in the complete protection of the glucose/lactate metabolism of the cortex, but not of the inner ovarian mass. Perfusion without simultaneous submersion, resulted in partial protection of cortex, subcortex and medulla, while the combination of submersion and perfusion conveyed the highest level of protection for all three ovarian tissue layers.