Endocrinological and Metabolic Heterogeneity Is Low in Japanese Women With Polycystic Ovary Syndrome.

OBJECTIVES: This study aims to evaluate the endocrine differences among polycystic ovary syndrome (PCOS) phenotypes in Japanese women. METHODS: 118 Japanese women that we diagnosed with PCOS agreed to be included in the study. The study group was classified into the following 4 phenotypes: (A) hyperandrogenism (HA); ovulatory disorder (OvD) and polycystic ovary morphology (PCOM); (B) HA and OvD; (C) HA and PCOM; and (D) OvD and PCOM. We also recruited 66 healthy Japanese women to the study as control participants. Age, body mass index, androgens, luteinizing hormone, follicle-stimulating hormone, and insulin resistance (IR) index were evaluated and compared. RESULTS: The proportions of phenotypes A, B, C, and D were 57/120 (47.5%), 4/120 (3.3%), 13/120 (10.8%), and 46/120 (38.3%), respectively. The proportion of phenotype B was too small; therefore, phenotypes A and B were grouped as classical PCOS for intergroup comparisons. The luteinizing hormone/follicle-stimulating hormone ratio in the classical PCOS group was higher than that in the phenotype D group (P < 0.001). Androgen concentrations in the phenotype D group were significantly lower than those in the other groups (P < 0.01). Phenotype D was more common in lean women with PCOS. The surrogate marker of IR (homeostasis model assessment of IR) was not different irrespective of PCOS and its phenotypes. CONCLUSIONS: Except for androgens, endocrine differences by PCOS phenotype are not evident, suggesting that diversity among patients with PCOS is relatively low in Japanese women.

Cut-off value for anti-Müllerian hormone in the diagnostic criteria for polycystic ovary syndrome in the Japanese population.

AIM: To establish cut-off values for anti-Müllerian hormone (AMH) and antral follicle count (AFC) in the diagnostic criteria for polycystic ovary syndrome (PCOS) applicable to the Japan Society of Obstetrics and Gynecology (JSOG) 2024 criteria and the Rotterdam/International Evidence-Based Guideline for the assessment and management of PCOS (IEBG) 2023 criteria based on a nationwide survey, respectively, taking into account age, assays, and structure of the diagnostic criteria. METHODS: Data were collected for 986 PCOS cases and 965 control cases using a national survey in Japan and used to establish cut-off values for AMH and AFC. RESULTS: Serum AMH levels were significantly higher in the PCOS group compared to the control group. Serum AMH showed a significant negative correlation with age and significant positive correlation with AFC in both groups. In multiple regression analysis, serum AMH level was independently affected by AFC and total testosterone. AMH cut-off values suitable for the JSOG 2024 criteria and the Rotterdam/IEBG 2023 criteria were separately established for the 20-29 and 30-39 years of age groups, respectively, and for Access, Lumipulse and Elecsys/ECLusys, respectively. AFC cut-off values suitable for the JSOG 2024 criteria and Rotterdam/IEBG 2023 criteria were also established separately. AFC exhibited statistically greater variability than AMH. CONCLUSION: The serum AMH level is the biochemical representation of ovarian findings in PCOS and considered objective and highly reliable. Therefore, it could serve as a surrogate for AFC as a marker of polycystic ovarian morphology in diagnostic criteria.

Pregnancy-specific beta-1-glycoprotein 6 is a potential novel diagnostic biomarker of placenta accreta spectrum.

Early diagnosis is essential for the safer perinatal management of placenta accreta spectrum (PAS). We used transcriptome analysis to investigate diagnostic maternal serum biomarkers and the mechanisms of PAS development. We analyzed eight formalin-fixed paraffin-embedded placental specimens from two placenta increta and three placenta percreta cases who underwent cesarean hysterectomy at Sapporo Medical University Hospital between 2013 and 2019. Invaded placental regions were isolated from the uterine myometrium and RNA was extracted. The transcriptome difference between normal placenta and PAS was analyzed by microarray analysis. The PAS group showed markedly decreased expression of placenta-specific genes such as LGALS13 and the pregnancy-specific beta-1-glycoprotein (PSG) family. Term enrichment analysis revealed changes in genes related to cellular protein catabolic process, female pregnancy, autophagy, and metabolism of lipids. From the highly dysregulated genes in the PAS group, we investigated the expression of PSG family members, which are secreted into the intervillous space and can be detected in maternal serum from the early stage of pregnancy. The gene expression level of PSG6 in particular was progressively decreased from placenta increta to percreta. The PSG family, especially PSG6, is a potential biomarker for PAS diagnosis.

Clinical application of long-read nanopore sequencing in a preimplantation genetic testing pre-clinical workup to identify the junction for complex Xq chromosome rearrangement-related disease.

OBJECTIVE: Xq chromosome duplication with complex rearrangements is generally acknowledged to be associated with neurodevelopmental disorders, such as Pelizaeus-Merzbacher disease (PMD) and MECP2 duplication syndrome. For couples who required a PGT-M (pre-implantation genetic testing for monogenic disease) for these disorders, junction-specific PCR is useful to directly detect pathogenic variants. Therefore, pre-clinical workup for PGT-M requires the identification of the junction of duplicated segments in PMD and MECP2 duplication syndrome, which is generally difficult. METHODS: In this report, we used nanopore long-read sequencing targeting the X chromosome using an adaptive sampling method to identify breakpoint junctions in disease-causing triplications. RESULTS: By long-read sequencing, we successfully identified breakpoint junctions in one PMD case with PLP1 triplication and in another MECP2 triplication case in a single sequencing run. Surprisingly, the duplicated region involving MECP2 was inserted 45 Mb proximal to the original position. This inserted region was confirmed by FISH analysis. With the help of precise mapping of the pathogenic variant, we successfully re-established STR haplotyping for PGT-M and avoided any potential misinterpretation of the pathogenic allele due to recombination. CONCLUSION: Long-read sequencing with adaptive sampling in a PGT-M pre-clinical workup is a beneficial method for identifying junctions of chromosomal complex structural rearrangements.

Prenatal alcohol exposure and adverse fetal growth restriction: findings from the Japan Environment and Children's Study.

BACKGROUNDS: Japanese studies on the association between maternal alcohol consumption and fetal growth are few. This study assessed the effect of maternal alcohol consumption on fetal growth. METHODS: This prospective birth cohort included 95,761 participants enrolled between January 2011 and March 2014 in the Japan Environment and Children's Study. Adjusted multiple linear and logistic regression models were used to assess the association between prenatal alcohol consumption and infant birth size. RESULTS: Consumption of a weekly dose of alcohol in the second/third trimester showed a significant negative correlation with standard deviation (SD; Z) scores for body weight, body length, and head circumference at birth, respectively. Consumption of a weekly dose of alcohol during the second/third trimester had a significant positive correlation with incidences of Z-score ≤ -1.5 for birth head circumference. Associations between alcohol consumption in the second/third trimester and Z-score ≤ -1.5 for birth weight or birth length were not significant. Maternal alcohol consumption in the second/third trimester above 5, 20, and 100 g/week affected body weight, body length, and head circumference at birth, respectively. CONCLUSION: Low-to-moderate alcohol consumption during pregnancy might affect fetal growth. Public health policies for pregnant women are needed to stop alcohol consumption during pregnancy. IMPACT: This study examined the association between maternal alcohol consumption and fetal growth restriction in 95,761 pregnant Japanese women using the prospective birth cohort. Maternal alcohol consumption in the second/third trimester more than 5, 20, and 100 g/week might affect fetal growth in body weight, body length, and head circumference, respectively. The findings are relevant and important for educating pregnant women on the adverse health effects that prenatal alcohol consumptions have on infants.

Self-administration of gender-affirming hormones and supratherapeutic dosing are relatively common in Japanese transgender women.

AIM: This study was performed to determine the proportion of transgender women with self-adjusted hormone administration and excess dosing. METHODS: The medical records of 87 transgender women who visited our gender clinic from 2010 through 2019 were reviewed. The complete blood count and serum concentrations of D-dimer, gonadotropins, and sex steroids were compared between transgender women who were self-administering gender-affirming hormones and women not using such hormones. RESULTS: Fifty-eight of 87 (66.7%) transgender women had contravened the guideline and self-adjusted their hormone administration. The hormonal data of one woman with hypopituitarism were eliminated from the analyses. The serum gonadotropin and testosterone levels were significantly lower in the self-administration group than in the hormone-naïve group. Gonadotropin levels below the lower limit of normal were found in 32/86 (37.2%) transgender women. The testosterone levels in six transgender women were not analyzed because these women had undergone sex reassignment surgery before visiting our hospital. Testosterone levels below the lower limit of normal men were found in 36/80 (45.0%) transgender women. Unexpectedly, 29/36 (80.6%) transgender women who were classified as having suppressed serum testosterone levels had testosterone levels of <0.6 ng/mL, which corresponds to the levels in cisgender women. The white blood cell count and hemoglobin concentration were significantly different between the groups. CONCLUSION: Self-initiated hormonal treatments seem to affect the serum concentrations of gonadotropin and sex steroids and the complete blood count. The prevalence of transgender women with self-adjusted use of gender-affirming hormones is high, and an excess dose of hormones occasionally occurs.

Mediating Factors Between Parental Socioeconomic Status and Small for Gestational Age in Infants: Results from the Hokkaido Study on Environment and Children's Health.

OBJECTIVES: Previous studies indicated a significant association between small for gestational age (SGA) in infants and their parents' socioeconomic status (SES). Thus, this study aimed to examine if parental factors, such as maternal smoking, and the pre-pregnancy body mass index (BMI) could mediate the associations between parental SES and SGA. METHODS: The participants of this study were pregnant women who enrolled in an ongoing birth cohort study, the Hokkaido study, during the first trimester of their pregnancies. A total of 14,593 live singleton births were included in the statistical analysis, of which 1011 (6.9%) were SGA. Two structural equation models were employed to evaluate the associations between parental SES, parental characteristics, and SGA. RESULTS: The effect of low SES on SGA was directly mediated by maternal pre-pregnancy BMI, smoking during the third trimester, and alcohol consumption during the first trimester in the first model, which was based the assumption of independent associations between mediating factors. In the second model, which additionally considered the mediating factors from the first model, smoking during pregnancy mediated decline in parental SES, consequently increased SGA. Moreover, an increase in pregnancy smoking status increased the prevalence of lower maternal pre-pregnancy BMI and its effect on SGA. CONCLUSIONS FOR PRACTICE: In this study, we observed the independent mediating effect of maternal pre-pregnancy BMI, smoking, and alcohol consumption during pregnancy on low SES and, consequently, SGA, with the additional mediating pathway of SES to smoking to low BMI on SGA.

What is the most anticipated change induced by treatment using gender-affirming hormones in individuals with gender incongruence?

OBJECTIVES: To identify the most eagerly anticipated change resulting from hormone therapy using gender-affirming hormones for patients with gender incongruence undergoing a clinical trial. METHODS: Patients diagnosed with gender identity disorders based on the International Classification of Diseases 10th revision classification at three institutions in Japan for whom hormone therapy using gender-affirming hormones was initiated were analyzed. They were asked what the most anticipated change was due to gender-affirming hormone that they had thought of between giving informed consent and the first administration of the drug. RESULTS: The responders were 336 transgender men who were administered androgens and 48 transgender women who received estrogens. The median age at commencement of hormone therapy was 24 years for transgender men and 28 years for transgender women. For transgender men, the most frequent answer was cessation of menses (52.7%) followed by a deepened voice (32.4%). For transgender women, breast development (35.4%) was the most anticipated change, followed by gynoid fat deposition (29.2%). CONCLUSIONS: Cessation of menses in transgender men and breast development/gynoid fat deposition in transgender women might represent primary end-points in clinical trials evaluating the efficacy of hormonal treatment in these patients.

Association Between Maternal Serum Folate Concentrations in the First Trimester and the Risk of Birth Defects: The Hokkaido Study of Environment and Children's Health.

BACKGROUND: Low red blood cell folate concentrations during early pregnancy might cause neural tube defects. However, the association between folate concentrations and birth defects of other neural crest cell-derived organs remains unknown. We investigated the associations between birth defects and first-trimester serum folate concentrations in a birth-cohort study in Japan. METHODS: In total, 14,896 women who were prior to 13 weeks of gestation were enrolled from 2003 through 2012. Birth defect information was obtained from medical records and questionnaires. The association between folate levels in the first trimester and birth defects categorized as ICD-10 cord defects and neural crest cell-derived organ defects was examined. The crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) per log-transformed folate concentration were calculated using logistic regression. RESULTS: Blood samples were obtained at a mean of 10.8 weeks of gestation. Median serum folate level was 16.5 (interquartile range, 13.4-21.5) nmol/L, and the deficiency level (less than 6.8 nmol/L) was 0.7%. There were 358 infants with birth defects. The adjusted odds ratio for any birth defect, ventricular septal defects, and cleft lip was 0.99 (95% CI, 0.74-1.32), 0.63 (95% CI, 0.30-1.33), and 4.10 (95% CI, 0.96-17.58), respectively. There were no significant associations between first-trimester maternal serum folate and the risk of birth defects. CONCLUSIONS: We were unable to demonstrate a relationship between maternal serum folate in the first trimester and birth defects. Potential confounding factors may have influenced our results.

Obstetrical prognosis of patients who underwent vaginal radical trachelectomy during pregnancy.

AIM: Radical trachelectomy (RT) with pelvic lymphadenectomy has become an option for young patients with early invasive uterine cervical cancer who decide to maintain their fertility. However, this operative method entails a high risk for the following pregnancy due to its radicality. Therefore, RT for pregnant patients can be a challenge both for gynecologic oncologists and obstetricians. METHODS: We have performed vaginal RT for five pregnant patients with uterine cervical cancer stage 1B1 according to the method of Dargent et al. The operations were performed between 16 and 26 weeks of pregnancy, and the patients were followed up carefully according to the follow-up methods we reported previously. RESULTS: Vaginal RT was performed for five patients without any troubles. Four of the patients continued their pregnancies until almost 34 weeks or longer under our previously published follow-up schedule. The pregnancy of one patient was terminated at 26 weeks due to recurrence of the cancer. CONCLUSION: Expansion of vaginal RT for pregnant patients with uterine cervical cancer could be a practical option for pregnant patients with early invasive uterine cervical cancer.

Prevalence and Risk of Birth Defects Observed in a Prospective Cohort Study: The Hokkaido Study on Environment and Children's Health.

BACKGROUND: Prevalence rates of all anomalies classified as birth defects, including those identified before the 22nd gestational week, are limited in published reports, including those from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). In our birth cohort study, we collected the data for all birth defects after 12 weeks of gestation. METHODS: Subjects in this study comprised 19,244 pregnant women who visited one of 37 associated hospitals in the Hokkaido Prefecture from 2003 through 2012, and completed follow-up. All birth defects after 12 weeks of gestation, including 55 marker anomalies associated with environmental chemical exposures, were recorded. We examined parental risk factors for birth defects and the association between birth defects and risk of growth retardation. RESULTS: Prevalence of all birth defects was 18.9/1,000 births. The proportion of patients with birth defects delivered between 12 and 21 weeks of gestation was approximately one-tenth of all patients with birth defects. Among those with congenital malformation of the nerve system, 39% were delivered before 22 weeks of gestation. All patients with anencephaly and encephalocele were delivered before 22 weeks of gestation. We observed different patterns of parental risk factors between birth defect cases included in ISBDSR and cases not included. Cases included in ISBDSR were associated with an increased risk of preterm birth. Cases not included in ISBDSR were associated with an increased risk of being small for gestational age at term. CONCLUSIONS: Data from our study complemented the data from ICBDSR. We recommend that birth defects not included in ICBDSR also be analyzed to elucidate the etiology of birth defects.

Transabdominal cerclage (TAC) for patients with ultra-short uterine cervix after uterine cervix surgery and its impact on pregnancy.

AIM: Patients with an ultra-short uterine cervix as a result of large conization, repeated conization or radical trachelectomy (RT), are at high risk of preterm premature rupture of the membrane, which leads to preterm birth. We have commenced performing transabdominal cerclage (TAC) of the uterine cervix for these patients. In this study, we examined the safety of TAC and its impact on pregnancy. METHODS: We have performed TAC in 11 patients before pregnancy: in six after large cervical operations, such as repeated conization; and in five for difficulties with cervical cerclage after RT. After laparotomy, a Teflon thread was placed in the avascular space between the uterine vessels and the uterine muscle, and tied. The clinical course of the patients after TAC and their pregnancy course were retrospectively reviewed. RESULTS: TAC was performed safely without any complications. The mean operative duration was 53 ± 10 min, and the mean blood loss during the operation was 49 ± 64 mL. Seven women conceived within 2 years after TAC. Their pregnancy courses were favorable. Five of the women underwent scheduled cesarean sections, while two pregnancies are ongoing. CONCLUSIONS: Although there are risks of various complications as a result of the use of non-absorbable thread and the need for two extra laparotomies, TAC can be a safe and useful option for patients who show cervical incompetence after large uterine cervical operations, such as RT or large conization.

Rare case of occult testosterone-producing ovarian tumor that was diagnosed by selective venous hormone sampling.

CASE: A 32 year old woman was referred because of secondary amenorrhea, hirsutism, and voice deepening. OUTCOME: The blood testosterone level was markedly high. A transvaginal ultrasound revealed a small region in the left ovary, but whether or not it was a tumor was unclear. Therefore, selective ovarian venous sampling was performed. Consequently, the testosterone level was selectively increased in a blood sample that was taken from the left ovarian vein, the tumor was successfully localized, and a laparoscopic left oophorectomy was performed. Although the left ovary appeared to be normal at laparoscopy, the androgen-secreting tumor was located within it. The tumor was diagnosed as a Leydig cell tumor by histopathological analyses. CONCLUSION: This report demonstrates that selective blood sampling from ovarian veins before an operation is effective in localizing an androgen-producing ovarian tumor that is difficult to diagnose by imaging studies.

Possibility of less radical treatment for patients with early invasive uterine cervical cancer.

AIM: Radical trachelectomy (RT) with lymphadenectomy has become a standard treatment modality for patients with early invasive uterine cervical cancer who hope to preserve fertility. However, pregnancy after RT has high risks of preterm birth. The possibility of more conservative RT and the application of RT for patients with higher clinical stages were studied. METHODS: The medical charts and specimens of 42 patients who underwent RT and 64 patients who underwent radical hysterectomy were retrospectively studied. Tumor size, distance between the margin of the cancer and the internal orifice of the uterus (os), parametrial invasion, lymph node metastasis and prognoses were investigated. RESULTS: The average distances between the inner margin of the cancer and the internal os were 37 mm, 29 mm, 18.7 mm and 14 mm for patients with stage 1 A2, 1B1 (≤ 2 cm), 1B1 (> 2 cm) and 1B2, respectively. When amputation was performed 10 mm below the internal os, all 10 patients with 1 A2, 57 with 1B1 (≤ 2 cm), 19 with 1B1 (> 2 cm), and one with 1B2 had a cancer-free margin > 10 mm. Patients with stage 1 A2 had a cancer-free margin > 10 mm even if we amputated the cervix 20 mm below the internal os. Parametrial invasion was detected in two patients with stage 1B1. CONCLUSIONS: A simple trachelectomy 20 mm below the internal os with pelvic lymphadenectomy might be possible for stage 1 A2 patients. The present method is best for stage 1B1 patients (≤ 2 cm). RT for stage 1B1 (>2 cm) or higher stages should be contraindicated.

Obstetrical prognosis of patients with cervical intraepithelial neoplasia (CIN) after "coin-shaped" conization.

PURPOSE: Uterine cervical conization is related to adverse pregnancy outcomes in subsequent pregnancies. To deal with this problem, we started conservative coin-shaped conization for reproductive-aged patients with cervical intraepithelial neoplasia (CIN). Here we report both the obstetrical and oncological impacts of this operation in comparison with the standard cone-shaped resection. METHODS: A total of 401 women 44 years old or younger were treated in our hospital by CO2 laser conization between 2003 and 2012, and subsequently 50 patients became pregnant. The patients were divided into two groups, a standard cone-shaped conization group (until 2008) and a shallow coin-shaped conization group (beginning in 2008). The pregnancy courses and oncological prognoses of these two groups were studied. RESULTS: Cone height reduction of about 3 mm was done. However, there were no significant differences between the two groups with regard to the occurrence of oncological complications. In the standard conization group, 18 of the 25 patients delivered at term. In the coin-shaped conization group, 20 of the 25 patients delivered at term. There were no significant differences between the two groups with regard to the occurrence of various obstetrical complications. However, the reduction rate of cervical length over the pregnancy was smaller in the coin-shaped group and the number of patients with a short cervix length of 2 cm or less was smaller in the coin-shaped group. CONCLUSIONS: Although conservative coin-shaped conization did not markedly improve the obstetrical prognosis, this operative procedure improved the reduction rate of uterine cervical length over the pregnancy without any increase in oncological complications.

Successful delivery after transabdominal cerclage of uterine cervix for cervical incompetence after radical trachelectomy.

Pregnancy after radical trachelectomy (RT) has a high risk of prematurity and complications such as preterm premature rupture of the membrane and chorioamnionitis. Placing a cervical cerclage at the time of RT plays an important role in preventing such obstetrical complications. In patients who have trouble with the cervical cerclage, miscarriage during the second trimester seems to be inevitable. We have therefore started preconception transabdominal cerclage (TAC) for these patients. A 36-year-old Japanese woman who had a history of miscarriage due to trouble with the nylon thread used for cerclage, successfully delivered after TAC. TAC is a useful treatment modality to prevent miscarriage for patients who have trouble with cerclage after RT.

Importance of uterine cervical cerclage to maintain a successful pregnancy for patients who undergo vaginal radical trachelectomy.

BACKGROUND: We have performed 36 vaginal radical trachelectomies (RTs) for patients with early invasive uterine cervical cancer and experienced 10 deliveries. Pregnancy after RT has far higher risks of prematurity and complications such as preterm premature rupture of the membrane (pPROM) and chorioamnionitis. We report the significance of transabdominal cerclage in the follow-up of pregnancy after vaginal RT. METHODS: Our operative procedure is based on that of Dargent et al. We amputated the cervix approximately 10 mm below the isthmus. For the removal of the parametrium, we cut at the level of type II hysterectomy. A nylon suture is also placed around the residual cervix. Pregnancy courses after vaginal RT were studied in 9 patients (10 pregnancies) with respect to cervical length and several infectious signs. RESULTS: Obstetric prognosis after RT was improved with our follow-up modality. Four patients who were followed up with this modality were able to continue their pregnancies until late in the third trimester. However, it was not effective for four patients who showed cervical incompetence due to slack cerclage. They suffered from pPROM without any infectious signs and uterine contraction. Though we performed transabdominal uterine cervical cerclage for one patient in her 19th week of pregnancy, it was unsuccessful. CONCLUSIONS: Cervical cerclage placed at the time of RT played an important role in preventing dilatation of the uterine cervix and the subsequent occurrence of pPROM. Transabdominal cervical cerclage should be performed earlier in pregnancy or before pregnancy in patients who have experienced problems with cervical cerclage.

Continuous high-dose estrogen controls serum FSH and LH levels: new treatment strategy for extremely low ovarian reserve patients, two case reports.

At present, there are no proven therapies to improve ovarian function in women with premature ovarian insufficiency (POI) or in those with extremely low ovarian reserve (LOR). We report successful IVF outcomes achieved with continuous high-dose estrogen supplementation in patients with LOR. Patients were 33- and 42-year-old nulligravidae with high-serum FSH (over 30 IU/L) and undetectable serum AMH (under 0.1 ng/mL) levels; however, neither patient fulfilled the diagnostic criteria for POI. After cycle cancellation and unsuccessful IVF treatment, both patients received conjugated estrogen (CE) supplementation (2.5-3.75 mg/day) from day 2 of their menstrual cycle to the day of HCG administration in their IVF treatment cycles. Following continuous high-dose estrogen supplementation, oocytes were successfully retrieved from both patients and fertilized. Both patients also achieved ongoing pregnancy through frozen-thawed embryo transfer cycles. In conclusion, high-dose estrogen supplementation down-regulated serum FSH and LH within their physiological ranges, which led to functional follicle growth and prevented early luteinization. Further studies will be needed to confirm the effect of this treatment on POI patients and to establish a new and individualized protocol for LOR patients.

Excessive androgen exposure in female-to-male transsexual persons of reproductive age induces hyperplasia of the ovarian cortex and stroma but not polycystic ovary morphology.

STUDY QUESTION: Does administration of androgen to female-to-male transsexual persons (FTMs) of reproductive age induce polycystic ovary (PCO) morphology? SUMMARY ANSWER: Administration of high-dose androgen to women causes pathognomonic changes to the ovarian cortex and stroma that resemble Stein-Leventhal syndrome but it does not induce PCO morphology. WHAT IS KNOWN ALREADY: Androgen is thought to play a key role in follicular development and to be involved in the pathophysiology of polycystic ovary syndrome (PCOS). In several experimental models, animals given high-dose androgen show ovarian changes similar to those in women with PCOS. In previous human studies, the ovaries of FTMs who received androgen for long periods also exhibited PCO morphology. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective case-control study of women, all without PCOS, undergoing salpingo-oophorectomy. The case group consisted of 11 FTMs taking testosterone (duration range: 17 months to 14 years), while the control group consisted of 10 patients with gynaecologic malignancies who did not receive testosterone. PARTICIPANTS/MATERIALS, SETTING, METHODS: Resected ovaries from both groups were compared histologically with respect to changes in the cortex and stroma, and the number of follicles at each maturation stage. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with controls, the FTM group had a thicker ovarian cortex (P = 0.0001), and more hyperplastic collagen (P = 0.001), ovarian stromal hyperplasia (P = 0.003) and stromal luteinization, i.e. luteinized stromal cells with a small dark central nucleus surrounded by clear cytoplasm (P = 0.004). Isolated clusters of such stromal luteinized cells were found only in the testosterone-treated ovaries of FTMs. The number of primordial follicles was similar in the two groups (P = 0.22). The numbers of early stage (primary, pre-antral and early antral) follicles, which are dependent on androgen, were also similar (P = 0.81), as were the numbers of antral follicles (P = 0.97). In contrast, significantly greater numbers of atretic follicles were seen in the FTM than that in the control group (P = 0.01). LIMITATIONS, REASON FOR CAUTION: In addition to the low numbers in the study groups, the histological changes in FTMs were investigated after testosterone administration, therefore it is possible that some of the observed changes were already present, before androgen administration. WIDER IMPLICATION OF THE FINDINGS: Our results are at variance with those of earlier studies and suggest that excessive androgen exposure in women of reproductive age may not be a factor in the pathogenesis of PCOS.