Age-Related Changes in Low Serum Anti-Müllerian Hormone Levels in Female Adolescents: A Single-Center Retrospective Pilot Study.

STUDY OBJECTIVE: Available data on the clinical significance of low serum anti-Müllerian hormone (AMH) levels in female adolescents are limited. The aim of this study was to elucidate age-related changes in low serum AMH levels in adolescents and to identify predictive factors for AMH progression. METHODS: A retrospective review was conducted on a series of female adolescents aged 11-19 years with low serum AMH levels (<1.19 ng/mL) who underwent additional AMH tests at least 1 year apart. Participants who showed an increase in the subsequent AMH test (>1.6 ng/mL) (Group 1) were compared with those who did not (Group 2). RESULTS: Among 1655 adolescents who underwent AMH testing at least once from 2010 to 2022, 75 participants (4.5%) exhibited low AMH levels (<1.19 ng/mL), excluding primary ovarian insufficiency. A notable increase in serum AMH levels (>1.6 ng/mL) was confirmed in 7 (30.4%) of 23 female adolescents who underwent relevant follow-up testing. Group 1 had higher initial AMH levels and lower initial follicle-stimulating hormone levels than Group 2 (1.0 vs 0.59 ng/mL, P = .001 and 4.4 vs 9.8 mIU/mL, P = .015, respectively). Ovarian volume did not differ between the groups (3.8 vs 4.4 cm3, P = .465). None of the participants with initial AMH levels under 0.75 ng/mL showed an increase in AMH levels during follow-up. CONCLUSION: These findings suggest that low serum AMH levels in adolescents may have other explanations in addition to being indicative of a low ovarian reserve. Prospective studies involving a larger number of participants will aid in predicting AMH improvement in adolescents.

Etiology and Secular Trends in Primary Amenorrhea in 856 Patients: A 17-Year Retrospective Multicenter Study in Korea.

BACKGROUND: This study was performed to evaluate etiologies and secular trends in primary amenorrhea in South Korea. METHODS: This retrospective multi-center study analyzed 856 women who were diagnosed with primary amenorrhea between 2000 and 2016. Clinical characteristics were compared according to categories of amenorrhea (hypergonadotropic/hypogonadotropic hypogonadism, eugonadism, disorders of sex development) or specific causes of primary amenorrhea. In addition, we assessed secular trends of etiology and developmental status based on the year of diagnosis. RESULTS: The most frequent etiology was eugonadism (39.8%). Among specific causes, Müllerian agenesis was most common (26.2%), followed by gonadal dysgenesis (22.4%). Women with hypergonadotropic hypogonadism were more likely to have lower height and weight, compared to other categories. In addition, the proportion of cases with iatrogenic or unknown causes increased significantly in hypergonadotropic hypogonadism category, but overall, no significant secular trends were detected according to etiology. The proportion of anovulation including polycystic ovarian syndrome increased with time, but the change did not reach statistical significance. CONCLUSION: The results of this study provide useful clinical insight on the etiology and secular trends of primary amenorrhea. Further large-scale, prospective studies are necessary.

Management of non-obstetric traumatic vulvar haematoma: a retrospective review of 33 cases.

The cases of non-obstetric traumatic vulvar haematomas are rare, and there is a lack of consensus statements for the necessity of surgical intervention. We retrospectively analysed the data of 33 cases (mean age: 25.7 years) of non-obstetric traumatic vulvar haematoma (mean haematoma size: 8.4 cm). Women who underwent surgery (surgery group) were compared to those who received conservative management (conservative group). Twenty-four patients underwent surgery; most cases were of haematoma removal and primary closure. Nine patients received conservative management, such as ice bag application, antibiotics, or analgesia. The rate of deviation of the contralateral vulva because of haematoma was higher (54.2% versus 11.1%, p = .047) and the mean haematoma size was larger (9.5 versus 5.2 cm, p = .004) in the surgical than in the conservative group. While conservative management affects cases of minor vulvar haematoma, surgical evacuation of haematoma can be performed in cases of large haematoma (mean size: 9.5 cm), severe pain, distorted vulvar anatomy, and invisible urethral opening for indwelling urinary catheter.IMPACT STATEMENTWhat is already known on this subject? Cases of non-obstetric traumatic vulvar haematomas are rare. There are no consensus statements for the necessity of surgical intervention.What do the results of this study add? The study showed that surgical evacuation of haematoma can be performed in cases of large haematoma (mean size: 9.5 cm), severe pain, distorted vulvar anatomy, and invisible urethral opening for indwelling urinary catheter. Moreover, surgical management could hasten recovery.What are the implications of these findings for clinical practice and/or further research? The results of this study can be used in counselling non-obstetric traumatic vulvar haematomas. Further research is needed to confirm these findings.

Hyperandrogenic Milieu Dysregulates the Expression of Insulin Signaling Factors and Glucose Transporters in the Endometrium of Patients With Polycystic Ovary Syndrome.

PURPOSE: Subfertility associated with polycystic ovary syndrome (PCOS) mainly originates from oligoovulation/anovulation. Although insulin resistance and androgen excess are known to cause PCOS-associated implantation failure, the consequences of PCOS on endometrial homeostasis and pathophysiology have not been comprehensively understood. In this study, we examined whether the pathophysiologic milieu of PCOS intrinsically affects expression profiles of genes related to insulin signaling and facilitative glucose transporters (GLUTs) in the human endometrium and/or during in vitro decidualization. STUDY DESIGN: Seven healthy women with regular menstrual cycles and 13 patients with PCOS were recruited for this study. To mimic the hyperandrogenic or hyperinsulinemic milieu in the endometrium of patient with PCOS (PCOSE) in vitro, human endometrial stromal cells (hESCs) were treated with dihydrotestosterone (DHT) or insulin, respectively. RESULTS: In PCOSE, messenger RNA (mRNA) levels of insulin receptor (IR), IR substrate (IRS) 1, and IRS2 were significantly increased. Furthermore, GLUT1 and GLUT12 were aberrantly increased. Chronic exposure to insulin or DHT aberrantly increased IRS1/IRS2 phosphorylation and protein levels of GLUT1 and GLUT12 in hESCs, suggesting that not only hyperinsulinemic but also hyperandrogenic conditions affect insulin signaling and glucose metabolism. The mRNA microarrays demonstrated that DHT dysregulates various gene sets, including cell cycle and glucose metabolism, in hESCs. Furthermore, DHT suppressed the expression of GLUT1 and GLUT12 as well as decidualization markers, IGFBP1 and prolactin, during in vitro decidualization. CONCLUSIONS: The hyperandrogenic milieu affects gene expression profiles, including gene sets associated with insulin signaling, cell cycle, glucose metabolism, and/or glucose transport, in human endometrium and during in vitro decidualization.

Pituitary magnetic resonance imaging abnormalities in young female patients with hypogonadotropic hypogonadism.

OBJECTIVE: To elucidate the association between clinical and laboratory characteristics and pituitary magnetic resonance imaging (MRI) abnormalities in young female patients with hypogonadotropic hypogonadism (HH). METHODS: We retrospectively investigated a series of 74 female patients (age range, 14-42 years) with normoprolactinemic HH who underwent pituitary MRI. Pubertal milestones and hormonal features of patients with small pituitary glands (PGs) and space-occupying lesions were compared with those of patients with normal PGs. RESULTS: The overall frequency of abnormal PGs was 35.1%, with space-occupying lesions observed in 8 patients (10.8%), and small PG observed in 18 patients (24.3%). The mean serum gonadotropin level was not different between patients with and without pituitary MRI abnormalities (P>0.05). Space-occupying lesions were not associated with low gonadotropin levels, type of amenorrhea, or presence of secondary sex characteristics. The frequency of space-occupying lesions was higher in patients with interrupted puberty (25.0%) than in patients who did not go through puberty (4.8%) or had a normal puberty (9.8%), but were not statistically significant (P>0.05). Small PG was associated with low gonadotropin levels and type of amenorrhea (P<0.05). CONCLUSION: Clinically significant space-occupying lesions were not associated with low gonadotropin levels, type of amenorrhea, or presence of secondary sex characteristics. However, the frequency of space-occupying lesions was higher in patients with interrupted puberty than in patients who did not go through puberty or who with normal puberty.

Hyperandrogenic Milieu Dysregulates the Expression of Insulin Signaling Factors and Glucose Transporters in the Endometrium of Patients With Polycystic Ovary Syndrome.

PURPOSE:: Subfertility associated with polycystic ovary syndrome (PCOS) mainly originates from oligoovulation/anovulation. Although insulin resistance and androgen excess are known to cause PCOS-associated implantation failure, the consequences of PCOS on endometrial homeostasis and pathophysiology have not been comprehensively understood. In this study, we examined whether the pathophysiologic milieu of PCOS intrinsically affects expression profiles of genes related to insulin signaling and facilitative glucose transporters (GLUTs) in the human endometrium and/or during in vitro decidualization. STUDY DESIGN:: Seven healthy women with regular menstrual cycles and 13 patients with PCOS were recruited for this study. To mimic the hyperandrogenic or hyperinsulinemic milieu in the endometrium of patient with PCOS (PCOSE) in vitro, human endometrial stromal cells (hESCs) were treated with dihydrotestosterone (DHT) or insulin, respectively. RESULTS:: In PCOSE, messenger RNA (mRNA) levels of insulin receptor (IR), IR substrate (IRS) 1, and IRS2 were significantly increased. Furthermore, GLUT1 and GLUT12 were aberrantly increased. Chronic exposure to insulin or DHT aberrantly increased IRS1/IRS2 phosphorylation and protein levels of GLUT1 and GLUT12 in hESCs, suggesting that not only hyperinsulinemic but also hyperandrogenic conditions affect insulin signaling and glucose metabolism. The mRNA microarrays demonstrated that DHT dysregulates various gene sets, including cell cycle and glucose metabolism, in hESCs. Furthermore, DHT suppressed the expression of GLUT1 and GLUT12 as well as decidualization markers, IGFBP1 and prolactin, during in vitro decidualization. CONCLUSIONS:: The hyperandrogenic milieu affects gene expression profiles, including gene sets associated with insulin signaling, cell cycle, glucose metabolism, and/or glucose transport, in human endometrium and during in vitro decidualization.

Age at menarche in Korean adolescents: trends and influencing factors.

BACKGROUND: An increased incidence of central precocious puberty has been recently reported in South Korea, which suggests an ongoing downward trend in pubertal development in the Korean population. We aimed to verify the trend in age at menarche in young Korean women during the last decade and associated factors. METHODS: We analyzed a population-based sample of 3409 Korean girls, aged 10-18 years, using data from the Korean National Health and Nutrition Examination Surveys (KNHANES) II (2001), III (2005), IV (2007-2009), and V (2010 and 2011). Average age at menarche was studied using the Kaplan-Meier survival method and predictors were analyzed using Cox proportional hazards model. The percentage of subjects who had experienced menarche at each age level was compared by using the Cochran-Armitage test. RESULTS: Overall mean age at menarche was 12.7 years. The percentage of subjects who experienced menarche before the age of 12 years was 21.4 % in 2001 but increased to 34.6 % in 2010/2011 (p < 0.01). In addition, the percentage of girls who experienced menarche before the age of 14 years increased from 76 % in 2001 to 92 % in 2010/2011 (p < 0.005). Adolescents whose mothers who had experienced early menarche (HR 1.48, 95 % CI [1.22-1.80]), and adolescents who were overweight (HR 1.24, 95 % CI [1.04-1.49]) were more likely to have experienced menarche. Additionally, underweight adolescents (HR 0.27, 95 % CI [0.12-0.60]) and adolescents who had a mother having late menarche (HR 0.68, 95 % CI [0.59-0.79]) were expected to have late menarche. None of the socioeconomic factors assessed in our study showed an association with age at menarche. CONCLUSIONS: A downward trend in age at menarche was defined in Korean adolescents during the last decade. Furthermore, influences of genetic and nutritional parameters on individual variance in age at menarche were defined.

Clinical and microbiologic characteristics of vulvovaginitis in Korean prepubertal girls, 2009-2014: a single center experience.

OBJECTIVE: To update information on the clinical and microbiologic characteristics of pediatric vulvovaginitis in Korean prepubertal girls. METHODS: A total of 120 girls (aged 0 to 9 years) with culture-confirmed pediatric vulvovaginitis, diagnosed between 2009 and 2014, were enrolled in the study. The epidemiologic and microbiologic characteristics, and clinical outcomes were assessed. Patients with sexual precocity, as well as those who were referred for suspected sexual abuse, were excluded. RESULTS: Girls aged 4 to 6 years were at the highest risk of pediatric vulvovaginitis. Seasonal distribution indicated obvious peaks in summer and winter. Of the 120 subjects, specific pathogens were identified in the genital specimens in only 20 cases (16.7%). Streptococcus pyogenes (n=12, 60%) was the leading cause of specific vulvovaginitis. Haemophilus influenzae was isolated in one patient. No cases presented with enteric pathogens, such as Shigella or Yersinia. A history of recent upper respiratory tract infection, swimming, and bubble bath use was reported in 37.5%, 15.8%, and 10.0% of patients, respectively. Recent upper respiratory tract infection was not significantly correlated with the detection of respiratory pathogens in genital specimens (P>0.05). Of 104 patients who underwent perineal hygienic care, 80 (76.9%) showed improvement of symptoms without antibiotic treatment. Furthermore, the efficacy of hygienic care was not significantly different between patients with or without specific pathogens (P>0.05). CONCLUSION: Specific pathogens were only found in 16.7% of pediatric vulvovaginitis cases. Our results indicate an excellent outcome with hygienic care, irrespective of the presence of specific pathogens.

Magnetic resonance imaging-guided focused ultrasound surgery for symptomatic uterine fibroids: estimation of treatment efficacy using thermal dose calculations.

OBJECTIVE: To study the correlation between the predicted thermal dose volume (TDV) and the actual ablation volumes in MR-guided focused ultrasound surgery (MRgFUS) for symptomatic uterine fibroids, and to follow up the outcome for 12 months post-treatment. STUDY DESIGN: Phase-difference fast spoiled gradient-echo MR images were used to analyze thermal change during the energy deliveries of MRgFUS in 60 consecutive patients treated for symptomatic uterine fibroids. The TDV obtained through analysis of these MR images was compared with the non-perfused volume (NPV) measured on post-treatment contrast enhanced T1-weighted images. Final values of TDV ratio and NPV ratio were obtained by dividing these values by original fibroid volume. Patients were followed for 12 months post-treatment to assess symptomatic relief using the symptom severity score (SSS). RESULTS: Treatments in which we managed to reach a TDV ratio larger than 27% of the treated fibroid yielded a ratio of NPV to TDV of 1.1±0.5, indicating accurate control of the non-invasive procedure. Patient symptoms, as measured by the SSS, continuously decreased from a mean baseline score of 50±22 to 19±12 (P<0.0001) 12 months post-treatment. CONCLUSIONS: At large treatment volumes (exceeding 27% TDV ratio), thermal dose estimates correspond very closely to non-perfused volumes measured immediately post treatment. These large treatment volumes result in continuous clinical improvement throughout the first 12 months after MRgFUS.

Homozygous CYP17A1 mutation (H373L) identified in a 46,XX female with combined 17α-hydroxylase/17,20-lyase deficiency.

BACKGROUND: Defects in cytochrome P450c17 are uncommon forms of congenital adrenal hyperplasia caused by CYP17A1 mutations. An H373L mutation in the CYP17A1 gene has been identified in Japanese and Chinese patients. This mutation impairs 17α-hydroxylase and 17,20-lyase activity. CASE: A 23-year-old Korean female (46,XX) presented with absent spontaneous puberty and hypertension. Hormonal findings were consistent with combined 17α-hydroxylase/17,20-lyase deficiency. Very high levels of progesterone and 11-deoxycorticosterone were detected, coincident with normal 17-hydroxysteroid levels. Plasma levels of dehydroepiandrosterone, androstenedione and testosterone were extremely low. Mutation analysis of the CYP17A1 gene identified a homozygous missense mutation changing His (CAC) to Leu (CTC) at codon 373. This mutation is known to completely abolish both 17α-hydroxylase and 17,20-lyase activity. The patient's nonconsanguineous parents were heterozygous for this mutation. Of note, her serum steroid levels indicated decreased, but still present, 17α-hydroxylase activity in vivo. CONCLUSION: We detected a homozygous H373L mutation in a patient with combined 17α-hydroxylase/17,20-lyase deficiency. Our findings demonstrate minimally preserved 17α-hydroxylase activity in vivo and contribute to our knowledge of the regional prevalence of this mutation in Northeast Asia.

Long-term results of symptomatic fibroids treated with uterine artery embolization: in conjunction with MR evaluation.

OBJECTIVE: The aim of the present study is to determine long-term clinical efficacy of uterine fibroid embolization (UFE) for symptomatic fibroids in conjunction with MR evaluation. MATERIALS AND METHODS: Sixteen patients with a follow-up period of 4 years or longer were analyzed retrospectively. Ages ranged from 27 to 45 (mean 39.5) years. Mean follow-up periods were 5.8 years (range: 4.1-6.9 years). The symptom changes, in terms of menorrhagia and dysmenorrhea and bulk-related symptoms, were assessed. The primary embolic agent was polyvinyl alcohol particle (250-710microm). All patients underwent preprocedural and long-term follow up MR imaging. Uterine volumes were calculated using MRI. RESULTS: Symptom improvements were reported for menorrhagia (8/9, 88.9%), dysmenorrhea (5/5, 100%), and bulk-related symptoms (7/9, 77.8%) at long-term follow up. Two patients (12.5%) had symptom recurrences at long-term follow-up. Tumor regrowth from incomplete infarction was a cause of recurrence in one patient and newly developed leiomyomas in the other one. One patient underwent hysterectomy because endometriosis developed 4 years after UFE. Of the 14 necrotic myomas on short-term follow up MR after UFE, eight (57.1%) demonstrated maintaining necrosis with further shrinkage and six (42.9%) were no longer visualized on long-term follow up MR images. Overall, the mean volume reduction rates of the predominant fibroid and uterus were 80.5%, 36.7% at long-term follow up, respectively. CONCLUSION: UFE is an effective treatment for symptomatic fibroids with an acceptable long-term success rate. Long-term MR imaging after UFE revealed persistent necrotic fibroid, non-visualization of fibroids and tumor regrowth when incompletely infarcted.

Long-term results of uterine artery embolization for symptomatic adenomyosis.

OBJECTIVE: Controversy exists regarding the effectiveness of uterine artery embolization (UAE) in the management of symptomatic adenomyosis. The aim our study was to determine the long-term clinical efficacy of UAE in the management of symptomatic adenomyosis without fibroids. MATERIALS AND METHODS: The cases of all patients who underwent UAE for adenomyosis without fibroids between 1998 and 2000 were analyzed. This study was a retrospective review of a prospectively collected database. Of the 66 patients, 54 patients with a follow-up period of 3 years or longer were enrolled in the study. Twelve patients were lost to follow-up. The patients' ages ranged from 29 to 49 years (mean, 40.2 years). The mean follow-up period was 4.9 years (range, 3.5-5.8 years). The primary embolic agent was polyvinyl alcohol particles (250-710 microm). All patients underwent MRI before UAE. Long-term follow-up MRI was performed on 29 patients; 22 of these patients had undergone short-term (3.5 months) follow-up MRI. Uterine volume was calculated with MR images. Symptom status in terms of menorrhagia and dysmenorrhea was scored on a scale of 0-10, 0 being no symptoms and 10 being the baseline, or initial symptoms. RESULTS: Thirty-one (57.4%) of the 54 women who underwent follow-up had long-term success. Four had immediate treatment failure, and 19 had relapses. Changes in mean menorrhagia and dysmenorrhea scores at long-term follow-up were -5.3 and -5.1, respectively (p < 0.001), representing significant relief of symptoms. The time between UAE and recurrence of symptoms ranged from 4 to 48 months (mean, 17.3 months). Five patients underwent hysterectomy because of symptom recurrence. Mean reduction in volume of the uterus was 26.3% at short-term follow-up and 27.4% at long-term follow-up. CONCLUSION: We found that UAE is effective in the management of symptomatic adenomyosis and has an acceptable long-term success rate. UAE should be considered a primary treatment method for patients with symptomatic adenomyosis. However, all patients should be given an explanation of the possibility of treatment failure, recurrence, and the need for hysterectomy.

Non-surgical treatment of vaginal agenesis using a simplified version of Ingram's method.

Non-surgical vaginal dilation is a safe and effective method for the creation of neovagina in the patient with vaginal agenesis. Compared to surgical methods, non-surgical vaginal dilation has the advantage of low morbidity, the creation of a more physiologic vaginal milieu, and no surgical scarring. To overcome some technical limitations of original Frank's method, in 1981 Ingram proposed a modification of the technique that used dilators of gradually increasing size mounted on a bicycle seat stool. Although several studies have shown satisfactory outcomes using Ingram's method, there are some practical difficulties in making and handling the bicycle seat stool. This article reports a case of a 24-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome whose vaginal agenesis is successfully treated with a simplified version of Ingram's method. This method uses dilators of gradually increasing size mounted on an ordinary chair instead of a bicycle seat stool. When necessary, the patient may use a fulcrum under the dilator.

Pregnancy following uterine artery embolization with polyvinyl alcohol particles for patients with uterine fibroid or adenomyosis.

PURPOSE: To determine whether uterine fibroid embolization (UFE) with polyvinyl alcohol (PVA) particles affects fertility in women desiring future pregnancy. METHODS: Of 288 patients managed with UFE with PVA particles for uterine myoma or adenomyosis between 1998 and 2001, 94 patients were enrolled in this study. The age range of participants was 20-40 years. The data were collected through review of medical records and telephone interviews. Mean duration of follow-up duration was 35 months (range 22-60 months). Patients using contraception and single women were excluded, and the chance of infertility caused by possible spousal infertility or other factors was disregarded. Contrast-enhanced magnetic resonance imaging was performed in all patients before and after UFE, and the size of PVA particles used was 255-700 mum. RESULTS: Among 94 patients who underwent UFE with PVA, 74 were on contraceptives, 6 had been single until the point of interview, and 8 were lost to follow-up. Of the remaining 6 patients who desired future pregnancy, 5 (83%) succeeded in becoming pregnant (1 patient became pregnant twice). Of a total of 8 pregnancies, 6 were planned pregnancies and 2 occurred after contraception failed. Five deliveries were vaginal, and 2 were by elective cesarean. Artificial abortion was performed in 1 case of unplanned pregnancy. There was 1 case of premature rupture of membrane (PROM) followed by preterm labor and delivery of an infant who was small-for-gestational-age. After UFE, mean volume reduction rates of the uterus and fibroid were 36.6% (range 0 to 62.6%) and 69.3% (range 36.3% to 93.3%), respectively. CONCLUSION: Although the absolute number of cases was small, UFE with PVA particles ultimately did not affect fertility in the women who underwent the procedure.

Uterine restoration after repeated sloughing of fibroids or vaginal expulsion following uterine artery embolization.

The aim of our study is to present our experience with uterine restoration after repeated sloughing of uterine fibroids or transvaginal expulsion following uterine artery embolization (UAE) and to determine its safety and outcome. One hundred and twenty-four women (mean age, 40.3 years; age range, 29-52 years) with symptomatic uterine fibroids were included in this retrospective study. We performed arterial embolization with poly(vinyl alcohol) particles (250-710 microm). Clinical symptoms and follow-up information for each patient were obtained through medical records. At an average of 3.5 months (range, 1-8 months) after embolization, magnetic resonance imaging examinations with T1- and T2-weighted and gadolinium-enhanced T1-weighted images were obtained for all patients. The mean follow-up duration was 120 days (90-240 days). Eight (6.5%) patients experienced uterine restoration after repeated sloughing of uterine fibroids or spontaneous transvaginal expulsion. The locations of the leiomyomas were submucosal (n=5), intramural (n=2) and transmural (n=1). The maximum diameter of the fibroids ranged from 3.5 to 18.0 cm, with a mean of 8.4 cm. The time interval from embolization to the uterine restoration was 7-150 days (mean 70.5 days). The clinical symptoms before and during vaginal sloughing or expulsion were lower abdominal pain (n=4), vaginal discharges (n=3), infection of necrotic myomas (n=2) and cramping abdominal pain (n=1). Gentle abdominal compression (n=1) and hysteroscopic assistance (n=1) were required to remove the whole fibroid. No other clinical sequelae, either early or delayed, were documented. Magnetic resonance images revealed the disappearance of leiomyomas, intracavitary rupture resulting in transformation of intramural or transmural myomas into submucosal myomas and localized uterine wall defects. Although the small size of this study precludes a strict conclusion, there appear to be few serious complications directly related to vaginal expulsion. Vaginal expulsion or fibroid sloughing is a possible course following UAE that is manageable, and the patients should be informed about this possibility.

Mutation analysis of the KAL gene in female patients with gonadotropin-releasing hormone deficiency.

Isolated gonadotropin-releasing hormone (GnRH) deficiency, including Kallmann's syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH), is a congenital disorder, which is characterized by a functional deficit in hypothalamic GnRH secretion. Despite recent advances in the understanding of the pathogenesis of the X-linked form of KS as the identification of the KAL gene (Xp22.3), the genetic basis of the sporadic form in female patients remains unclear. Although most searches for mutations in X chromosome have been reported in males, the newly recognized phenomenon of inheritance, such as genomic imprinting and uniparental disomy, raises the possibility of a female phenotype in the X- linked genetic defect. Here, the molecular study of the coding region of the KAL gene (exon 5 to 14) in 10 unrelated females with KS (n=6) or IHH (n=4) is reported. None of the subjects had familial histories of delayed puberty or hypogonadism. Samples from 4 healthy, unrelated female volunteers were used for identification of polymorphisms. PCR of the 10 exons of the KAL gene was performed on genomic DNA. The PCR products of the 10 exons were subject to single strand conformation polymorphism (SSCP) analysis to identify possible mutations. In an SSCP analysis of the amplified fragments (fragment size: 147 to 302 bp), no mutations or polymorphisms were found in any of the 10 patients and 4 controls. In conclusion, it is unlikely that KAL gene mutations are a clinically significant cause of sporadic GnRH deficiency in female patients, indicating the existence of defects in unidentified genes that result in the expression of the phenotypes in females.