47,Xxx in an adolescent with premature ovarian failure and autoimmune disease

Background: Premature ovarian failure (POF) is often associated with autoimmune disorders. The 47,XXX karyotype has also been associated with POF and other genitourinary abnormalities. Following is a case of a 17 year old with immune thrombocytopenic purpura (ITP), POF, 47, XXX and a positive antinuclear antibody (ANA).Case Report: A 17 year old Caucasian female was referred to the Adolescent Health Clinic for evaluation of oligomenorrhea with secondary amenorrhea. Thelarche occurred at 12 years, and menarche at 13 years of age. Since then she had a total of five menstrual periods, spaced 1-15 months apart and lasting 3-5 days. Her last menstrual period was six months prior to presentation. Past medical history was significant for chronic ITP diagnosed seven months prior to presentation, when she developed easy bruising. She was treated with IV gamma globulin and had a moderate response, but relapsed several weeks later. She was started on oral prednisone and had a good response, but continued to relapse whenever steroids were tapered. She was therefore maintained on prednisone 10 mg QOD. There was no family history of irregular menses or autoimmune disease. Physical exam revealed a well-appearing, slightly Cushingoid 17 year old. Physical and cognitive development were age-appropriate. There were no stigmata of Turner Syndrome. The thyroid was normal. Breasts were Tanner 5; public hair was Tanner 3. The external genitalia were normal and appeared well-estrogenized. The remainder of the exam was unremarkable. Pelvic ultrasound demonstrated a normal uterus and ovaries. Laboratory evaluation was significant for elevated gonadotropins and nondetectable estradiol. ANA was positive at 1:320 with a speckled pattern. Blood counts, serologies, complement levels, and coagulation studies were otherwise normal. Cytogenetic studies revealed a 47,XXX karyotype. The patient was placed on an estrogen/norethindrone hormone replacement patch for premature ovarian failure. To date, she has developed no further symptoms, and does not meet criteria for a diagnosis of systemic lupus erythematosis.Conclusions: A 47,XXX karyotype was found in a 17 year old with POF and ITP with a positive ANA. The presence of known autoimmune disease in a woman with POF should not dissuade the physician from evaluating for a potential genetic cause.     

Patients with 47, XXX karyotype who experienced premature ovarian failure (POF): two case reports

Purpose

Pubertal onset and sexual development are usually normal in 47, XXX individuals; however, we report two cases of premature ovarian failure (POF) in infertile women with trisomy X.

Methods

Chromosome analysis was conducted with G-banding and fluorescence in situ hybridization using X- and Y-bearing probe. Hormonal administration was primarily Kaufmann’s treatment or long-term estradiol treatment, followed by withdrawal bleeding from estrogen and progesterone.

Results

Two patients with trisomy X, aged 31 (patient 1) and 27 years (patient 2), were diagnosed with POF due to hypergonadotropic hypogonadism. Their ovaries were small. Patient 1 had a FSH level of 44.6 mIU/ml and patient 2 had a FSH level of 74.6 mIU/ml. In patient 1, with Kaufmann’s treatment, the FSH decreased to 13.5 mIU/ml; however, follicle growth did not occur following HMG stimulation. In patient 2, FSH did not decrease despite Kaufmann’s treatment; therefore, she was given a GnRH agonist and her FSH level decreased to 7.1 mIU/ml. However, her ovaries never responded to HMG stimulation.

Conclusion

We report on two patients with a 47, XXX karyotype who became infertile due to POF. We recommend that when a patient is diagnosed with trisomy X, the possibility of POF must be strongly considered.     

Non-chromosomal, non-iatrogenic premature ovarian failure in an adolescent population: a case series

STUDY OBJECTIVE: To review a cohort of patients with non-chromosomal, non-iatrogenic premature ovarian failure (POF) presenting to the Gynaecology Clinic of the Royal Children's Hospital, Melbourne. DESIGN: Case series SETTING: The Department of Gynaecology, Royal Children's Hospital, Melbourne, Victoria, Australia. PARTICIPANTS: Adolescent patients with non-chromosomal, non-iatrogenic premature ovarian failure RESULTS: Seventeen patients with non-chromosomal, non-iatrogenic POF were identified between 1990 and 2006. The average age at the time of diagnosis was 16.1 years. 58.8% (10/17) presented with primary amenorrhea, 23.5% (4/17) with secondary amenorrhea and 17.6% (3/17) with oligomenorrhea. 41.1% (7/17) were positive for anti-nucleic acid antibodies and one patient had antithyroid antibodies. Two sets of sisters were identified. CONCLUSION: Non-chromosomal, non-iatrogenic POF in an adolescent population is poorly characterized and its incidence unknown. It most commonly presents as primary amenorrhea, but may also present as a disturbance in a previously established menstrual cycle. Like adult onset POF, there appears to be an association with autoimmune conditions although, in our population, overt autoimmune conditions were rare. The occurrence of POF in two sets of sisters raises the possibility of a genetic basis of the condition being more significant in the younger age group, and provides an interesting cohort for further studies in the area.     

The role of genetic and autoimmune factors in premature ovarian failure

Purpose

To identify the role of both genetic (number of CGG repeats in the FMR1 gene) and autoimmune factors (anti-ovarian antibodies) in premature ovarian failure (POF).

Methods

In cross-sectional study, 78 women with POF were divided into 3 groups by the number of CGG repeats (less than 28, 28–36, more than 36) in any of the FMR1 gene alleles. We performed the detection of skewed X-chromosome inactivation, CGG repeats in the FMR1 gene, anti-ovarian antibodies (AOA) and sex hormones tests.

Results

Compared to a higher or lower number of CGG repeats the 28–36 triple CGG counts are strongly associated with the AOA detection (RR = 19.23, 95 % CI = 2.63–100.0). The women with autoimmune-driven POF have significantly higher anti-Mullerian hormone levels in comparison to women with non-autoimmune-driven POF.

Conclusion

The presence of AOA above 10 IU/mL is associated with the normal number of CGG repeats in regard to ovarian reserve and a better preservation of follicular primordial pool in the women with POF.     

Autoimmunity and premature ovarian failure

PURPOSE OF REVIEW: The different patterns of autoreactivity that may account for the premature infertility observed in patients with premature ovarian failure are described. RECENT FINDINGS: Animal model studies have detailed fundamental immune dysregulatory patterns that induce ovarian failure in the context of global polyglandular involvement, as well as autoimmune mechanisms that induce ovarian failure in the context of targeted ovarian pathology. Recent studies on premature ovarian failure patients implicate the ubiquitously expressed glycolytic enzyme, alpha-enolase, as a potential antigenic target, particularly in those patients with polyglandular involvement; and the ovarian-specific maternal-effect protein, Mater, whose expression is essential for fertility. SUMMARY: Several fundamentally distinct mechanisms may account for premature ovarian failure, including global immune dysregulation, particularly in patients with polyglandular autoimmunity. Premature ovarian failure may also be due to inflammatory autoimmunity targeted to ovarian-specific germline antigens (e.g., zona pellucida proteins or Mater) or differentiation/regulatory factors (e.g., inhibin-alpha). Moreover, the ovarian autoimmunity may be mediated by T cells (e.g., those targeting zona pellucida proteins) or B cells/antibodies (e.g., those targeting inhibin-alpha). Thus premature ovarian failure appears to be a complex disease entity with multiple underlying etiopathogenic contributions including the possibility of several distinctly different autoimmune mechanisms.     

Prenatal diagnosis of 47,XXX

We report 2 cases of 47,XXX that were diagnosed prenatally and were screened positive for trisomy 21 by biochemical and ultrasound markers. These cases underline the importance of discussing the sex chromosome abnormalities during the genetic counseling after an abnormal triple screen test or ultrasound examination.     

Premature ovarian failure: its relationship to autoimmune disease

Thirty-three patients with the diagnosis of chromosomally competent premature ovarian failure were reviewed for evidence of autoimmune disease. Thirty-nine percent of subjects had an associated autoimmune disorder, of which thyroid disease was the most common. One patient had vitiligo and one had adrenal insufficiency. A family history of autoimmune disease was elicited from 18% of subjects, all of whom proved to have an autoimmune disease themselves. From these findings, and a review of other studies, the authors conclude that an associated autoimmune disease, or other evidence of autoimmunity, is present in 30 to 50% of patients with premature ovarian failure.     

Chromosomal abnormalities in women with premature ovarian failure

Premature ovarian failure is a complex disorder that results in the early loss of ovarian function; however this disease must be separated from early menopause because these patients can sporadically ovulate and in literature are described pregnancies. The aetiology and the patho-physiology of premature ovarian failure are still matter of debate, but is commonly accepted that genetic factors play an important role. This review is aimed to present an overview of known inherited factor implied in the pathogenesis of this disorder to help physician in the counselling of affected pregnant women.     

Immunologic studies in patients with premature ovarian failure

Tests for a range of autoantibodies, and counts of lymphocytes, B cells, T cells, and T cell subsets were performed in 45 Chinese patients with premature ovarian failure and 45 age-matched normal control subjects. Eight patients (18%) were positive for at least one autoantibody. Only one patient was positive for antiovarian antibody. Patients with autoantibodies had a significantly higher percentage of circulating B cells. The lymphocyte, T cell, CD4+, and CD8+ counts in patients with premature ovarian failure were significantly higher than those in the control group, but the CD4:CD8 ratio was significantly lower in women with premature ovarian failure. There was a significant negative correlation between plasma estradiol levels and CD8+ counts, and a significant positive correlation between plasma estradiol levels and CD4:CD8 ratios. The changes in lymphocytes and lymphocyte subpopulations in premature ovarian failure may be due to estrogen deficiency.     

Poland's syndrome and premature ovarian failure

A 19-year-old female with Poland's Syndrome with associated left amastia, scoliosis, and left Sprengel deformity developed secondary amenorrhea from premature ovarian failure. Her menarche was at 13 years of age, and periods were regular and monthly until 15 years of age when her periods suddenly stopped. Her hormonal evaluation was significant for elevated FSH (46.5 mIU/ml) and LH (28.5 mIU/ml), and low estradiol (23 pg/ml). Anti-ovarian antibody level was less than 2 units (normal < 4 units). Her chromosomes were 46XX, by both standard karyotype and by fluorescence in situ hybridization. On transabdominal and transvaginal ultrasonography, ovaries were not visualized, the uterus was of normal size and anteverted and both kidneys were normal. The patient began hormone replacement therapy with conjugated estrogen (Premarin) 0.625 mg po daily and progestin (Provera) 5 mg on days 20 to 25. Because of menopausal symptoms, she was switched to a combination oral contraceptive (OC) with 20 mcg ethinyl estradiol that was eventually increased to 30 mcg. Her menopausal symptoms (hot flashes and sweating) improved on the continuous 30 mcg ethinyl estradiol combination OC. Following a comprehensive review of the literature, this is the first reported case of Poland's Syndrome associated with premature ovarian failure; however, this association may be coincidental.     

Autoimmunity in premature ovarian failure.

We performed laparoscopic ovarian biopsies in 17 of 19 cases with premature ovarian failure. Primordial follicles were found in three cases, corpora albicanti in two, and epithelial-lined cysts in two cases. Chromosome analysis revealed a normal 46XX karyotype in 15 patients, 46XY in two, 45XO in one, and 46XO/46XX mosaicism in one patient. Immunofluorescence studies were performed on ovarian tissue obtained by laparoscopic biopsy in 12 cases with premature ovarian failure. Blood serum was analyzed for circulating anti-ovary and other autoantibodies in all 12 cases. Circulating autoantibodies were found in the serum of six patients, but not in healthy controls. Direct immunofluorescence was positive in 5 of 12 ovarian tissue samples with predominantly vascular wall staining. Indirect immunofluorescence was positive in 10 of 12 cases; antibodies reacting with ovarian stromal components were present in eight cases, antibody reacting with follicular epithelium was present in one case, and antibodies reacting with nuclear antigens were present in five cases. Two of the patients had anti-thyroid microsomal antibodies, and one had antitesticular antibody. We conclude that a significant number of patients with ovarian failure have serologic and biopsy findings suggestive of and consistent with autoimmunity, even though there are no overt clinical manifestations of autoimmune disease.     

Incidence of premature ovarian failure

To assess the occurrence of premature ovarian failure, the age-specific incidence rates of natural menopause were determined for a cohort of 1858 women born between 1928 and 1932. These women were identified as Rochester, Minnesota residents in 1950 and were followed for date and type of menopause. A total of nine experienced natural menopause before age 40 years, which represents a 1% risk of natural menopause to age 40. The annual incidence rates of natural menopause per 100,000 person-years were ten for ages 15 to 29 and 76 for ages 30 to 39. In the age group 40 to 44, the incidence of natural menopause increased greatly to 881 per 100,000 person-years at risk.     

Bone loss in young women with premature ovarian failure

Objective: To evaluate the effect of premature ovarian failure on bone mineral density. Materials and methods: Forty-five women with karyotypically normal spontaneous premature ovarian failure underwent hip and spinal bone density measurements by dual energy X-ray absorptiometry. Findings were compared with a control group of 61 women of similar age. Results: The median (range) age of the women with premature ovarian failure was 33 (18–39) years. The median (range) time since diagnosis of premature ovarian failure was 2 years (0.5–7). Forty-one of the women (91%) had sought medical advice previously and had taken a variety of estrogen and progestin replacement regimens at least intermittently. Both the femoral neck bone mineral density measurements and the spinal bone mineral density measurements were significantly lower than measurements of the control group (P<0.05). Conclusion: Our study shows that premature ovarian failure has significantly lower levels of bone mineral density than the control group of normal women. We suggest that hormone replacement therapy should be substituted early and consistently in affected patients. Our data also raise questions about whether preservation of bone mass in these patients will require replacement of additional gonadal steroids.     

Acute oocyte loss in experimental autoimmune oophoritis as a possible model of premature ovarian failure

A high incidence of autoimmune oophoritis can be induced in (C57BL/6Cr x A/J)F1 mice that were thymectomized at 3 days of age. The vaginal opening day was significantly delayed (thymectomized mice [n = 35], 38.1 +/- 5.8 days [mean +/- SD] versus sham thymectomized mice [n = 26], 34.0 +/- 5.2 days; p less than 0.02). Most of the thymectomized mice showed irregular estrous cycles during the first several weeks and then fell into continuous diestrus. Local infiltration of mononuclear and plasma cells inside and around growing follicles was a prominent feature in the early stage of oophoritis. This abnormal feature was first noticed at 24 days of age and progressed in the follicular units. Acute loss of oocytes, especially of growing follicles, with massive mononuclear cell infiltration rapidly progressed after puberty, and atrophic ovaries with complete destruction of both primordial and growing follicles were then seen for 1 to 2 months after puberty. In mice with oophoritis, circulating autoantibodies against, ooplasm, zona pellucida, or steroid-producing cells were constantly detected by immunohistochemical assay. Autoimmune thyroiditis and gastritis accompanied by specific circulating antibodies were also detected in mice thymectomized at 3 days of age. This experimental model may serve as a tool for studying premature ovarian failure in humans.