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.     

Genetic aspects of premature ovarian failure: a literature review

Background  

The diagnosis of premature ovarian failure (POF) is based on the finding of amenorrhea before the age of 40 years associated with follicle-stimulating hormone levels in the menopausal range. It is a heterogeneous disorder affecting approximately 1% of women <40 years, 1:10,000 women by age 20 years and 1:1,000 women by age 30 years. POF is generally characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea).     

Pregnancy in a patient with resistant ovary syndrome--a case report

Resistant ovary syndrome (ROS) and premature ovarian failure (POF) represent two forms of hypergonadotropic hypogonadism. Principal symptoms include primary or secondary amenorrhea (before the age of 40 years), low levels of estradiol and elevated FSH (above 40IU/ml) in serum. The main difference is the presence of follicles in ROS which is tantamount to the possibility of pregnancy. We present the case of pregnancy in a 31-year-old patient who was initially diagnosed with POF, which was the basis of the final diagnosis of ROS.     

Etiology, clinical features and prognosis in secondary amenorrhea.

A clinical investigation of 356 patients with secondary amenorrhea revealed that 95% of patients with postpill amenorrhea and 56% of patients with anorexia nervosa recovered in 6 years. The corresponding recovery rates for patients with psychogenic amenorrhea and amenorrhea following self-induced weight loss were 72% for both groups, and in patients with the amenorrhea-galactorrhea syndrome and idiophatic functional amenorrhea the recovery rates at 6 years were 64 and 61% respectively. Unlike the other groups with functional amenorrhea, patients with the amenorrhea-galactorrhea syndrome had impaired ovarian responsiveness to exogenous gonadotropins. Bromocriptine treatment resulted in disappearance of the galactorrhea and restoration of the menses and/or ovulation in nine of 18 patients; of these three became pregnant. The effect of bromocriptine did not persist for long after treatment ceased, and permanent recovery was recorded only in four patients. The group with functional amenorrhea included 34 patients who wished to become pregnant. Gonadotropin treatment was successful in 20 patients, clomiphene-hCG in two, tamoxifen in two, bromocriptine in two, and combined bromocriptine and clomiphene in one. Thus, the overall pregnancy rate in patients with functional amenorrhea was 79%. The groups with ovarian amenorrhea inclutients with assumed ovarian failure responded to large doses of exogenous gonadotropins by ovulation and three became pregnant. Ovarian wedge resection was ineffective in all five cases with polycystic ovaries, but two patients became pregnant after treatment with clomiphene and chorionic gonadotropin, and one with exogenous gonadotropins.     

Idiopathic premature ovarian failure: clinical and endocrine characteristics

The characteristics of 26 patients with presumptive premature ovarian failure have been examined. The initial diagnosis was based on any single serum follicle-stimulating hormone (FSH) concentration of greater than 40 mIU/ml in karyotypically normal women under 35 years of age with irregular menses or amenorrhea. Clinical manifestations were heterogeneous: some failed to undergo pubertal maturation, and other developed hypergonadotropic amenorrhea following several years of regular menses. Almost 70% experienced hot flashes. Three had thyroiditis. Nine of 18 patients had hormonal evidence of functioning ovarian follicles, and 4 of 9 women had viable oocytes on biopsy. Evidence of ovulation was noted in five patients, and spontaneous pregnancy occurred in one. These data emphasize the fallacy of using elevated FSH levels to diagnose irreversible ovarian failure and indicate the possibility of ovulation and pregnancy in some affected individuals.     

Spontaneous pregnancies and premature menopause

Hypoestrogenic hypergonadotrophic amenorrhea occurring before the age of 40 years is generally considered irreversible. The term "premature menopause" used to define this condition seems a misnomer, and "premature ovarian failure" (POF) is preferred on both a psychological and a physiological basis. POF is not uncommon considering the incidence rate of 1-2% of women during their theoretically reproductive life. These circumstances are particularly painful when a child is desired. However, since a long time the notion of permanent cessation of ovarian function is challenged and intermittent and transient return of ovarian function has been described with 5-10% chance of pregnancy often more than 12 months after the beginning of the amenorrheic status. A multicentric retrospective study conducted by the GEDO reports 27 pregnancies out of 518 patients waiting for an in vitro fertilization with oocyte donation because of POF or occult ovarian insufficiency. Considering this work and a literature review, we try to propose part of understanding of the basic POF physiopathology, and to examine the factors which could act on the prognosis and the clinical management.     

Spontaneous pregnancy in a woman with premature ovarian failure: a case report

BACKGROUND: Women with premature ovarian failure often receive hormonal replacement therapy as part of the management strategy. However, it is very unusual for patients to become pregnant while on hormonal therapy. CASE: A 33-year-old woman with a history of infertility and secondary amenorrhea was diagnosed with premature ovarian failure. Part of her infertility workup included laparoscopy-hysteroscopy, a dye test with methylene blue, and endometrial and bilateral ovarian biopsy. Two months after completion of this procedure, the patient underwent sonography, which showed an intrauterine pregnancy at 14 weeks' gestation. The pregnancy continued to term, and a healthy infant was born. CONCLUSION: In most instances the etiology of premature ovarian failure is unknown. In rare cases this condition undergoes spontaneous, reversible remission. One interesting observation in our patient is that despite the performance of invasive diagnostic tests, there were minimal detrimental effects on the patient's pregnancy and infant. This case illustrates that the remote possibility of a spontaneous pregnancy in women with prema- ture ovarian failure should always be considered, and invasive diagnostic procedures should be performed when an intrauterine pregnancy is ruled out with certainty.     

Two successful pregnancies in a patient with chemotherapy-induced ovarian failure while on hormone replacement therapy

Chemotherapeutic agents administered for the treatment of malignancies can result in the incidence of premature ovarian failure (POF). Ovarian failure is reflected by elevated serum follicle-stimulating hormone (FSH) levels that may reach menopausal levels, at which the chances of a pregnancy are considered extremely rare. We report a case of a 26-year-old female who experienced two successful pregnancies, despite her diagnosis with chemotherapy-induced POF. This case suggests that patients who suffer from POF secondary to chemotherapy might still retain enough ovarian function with good quality oocytes that could support a healthy pregnancy.     

不孕患者卵巢功能早衰病因分析

目的:探讨不孕症患者卵巢功能早衰(POF)的病因特点。方法:回顾分析符合卵巢功能早衰诊断标准的不孕症121例的病因,其中有染色体结果者45例,对其进行详细分析。结果:(1)121例不孕的卵巢功能早衰患者中,有明确发病原因者14例(11.57%),其中行卵巢手术2例,服用卵巢毒性药物或有毒物接触史3例,染色体核型异常9例;(2)原发闭经6例,继发闭经115例,原发不孕95例(78.51%),继发不孕26例(21.49%),父母系近亲结婚3例。结论:卵巢功能早衰病因中染色体异常比例较高,对卵巢功能早衰患者行染色体检查很有必要;对不孕的POF患者开展遗传学研究具有重要的意义。     

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.     

24-year-old female with amenorhea: bilateral primary ovarian Burkitt lymphoma

OBJECTIVES: Burkitt's lymphoma (BL) occurs mostly in children. Isolated bilateral ovarian involvement presenting with amenorrhea is extremely rare in young adults. CASE: A 24-year-old female presented with secondary amenorrhea. Bilateral adnexal masses were identified on physical examination and abdominal computed tomography (CT). She underwent total abdominal histerectomy and bilateral salpingoophorectomy. Histopathologic evaluation yielded a diagnosis of BL of ovaries. Combined chemotherapy was administered. After complete remission an autologous bone marrow transplantation (ABMT) was performed. She died 35 days after ABMT. CONCLUSIONS: Although rare, BL should be kept in mind when isolated ovarian tumors are detected in young patients.     

The genetic basis of premature ovarian failure

Premature ovarian failure (POF) is a common condition, affecting approximately 1:100 women. It is characterised by amenorrhea, hypoestrogenism, and elevated gonadotrophin levels in women under the age of 40. It is often an unexpected and distressing diagnosis, which coincides with infertility and menopausal symptoms. There is a well recognised genetic basis to the development of POF. Our laboratory has identified several candidate genes associated with POF.     

Premature ovarian failure.

Premature ovarian failure (POF) is gonadal failure before the age of 40 years. Several rare causes have been discovered yet we still fail to identify the cause in many cases. Although it was once thought to be a permanent condition, a substantial number of patients experience spontaneous remissions and even pregnancy. HRT remains the cornerstone of treatment and the only proven method of achieving pregnancy in these patients is by ovum donation. New alternatives to HRT and fertility preservation are under development. Basic understanding of ovarian physiology and pathogenesis of POF is necessary for the development of newer therapies.     

Hormone replacement therapy at women with fertility problems and proofs of hypergonadotropic hypoovarism

The premature ovarian failure (POF), is the main precondition for the origin and the progress of the hypergonadotropic hypoovarism in part of the women with infertility. The significant decrease of the ovarian reserve, makes the treatment of these patients very difficult and problematic, still pregnancy is observed at 5-10% of them. Objective of the research: To study the effect of the Hormone Replacement Therapy (HRT) on the values of FSH before and after the treatment of women with POF, as well as its effect on the percentage of effective pregnancy. 47 infertile women with high values of FSH were included in the study and they followed a 2-4 month treatment with Trisequens tabl. The results of the ART were reported after the reduction of the FSH levels to the normal values. At the end of the treatment followed, the values of the FSH of 41 from 47 patients (87,23%), were reduced to normal range and necessary reproductive procedures were performed. Dividing the patients in 5 groups by age, it was found that the results depend to the greatest extend on this factor. In the group of women up to 30, pregnancy occurred in 25%, between 30 and 35 years this percentage decreased to 22,2%; in the group 35-40 years it sharply decreased to 10% and over 40 years the percentage was 0%. The total percentage of conceived patients for the whole last contingent is 13,4%. The patients with POF and high levels of FSH are worth to follow a Hormone Replacement Therapy before undertaking the oocyte donation.     

Case report: an identical twin with Sertoli-Leydig cell tumor

Our report details the workup and management of a 43-year-old woman with an identical twin who presented with 2 years of virilization and secondary amenorrhea. Serum total testosterone was elevated. An MRI did not identify adnexal or adrenal pathology. Subsequent ovarian vein sampling demonstrated unilateral testosterone elevation. The patient underwent laparoscopic unilateral oophorectomy resulting in the diagnosis of Sertoli-Leydig cell tumor (SLCT). Although SLCT is a rare sex-cord ovarian tumor, it is associated with endometrial hyperplasia and malignancy. Our goals are to review the workup of androgen-secreting tumors and discuss the clinical importance of the DICER1 mutation in the context of SLCT. In this case, an identical twin underwent DICER1 testing which was one of the essential steps in her clinical management.     

Results of human menopausal gonadotropin therapy at the Boston Hospital for Women (1979-1981)

To evaluate our results with induction of ovulation with human menopausal gonadotropins, we reviewed our experience from 1979 to 1981. Twenty-two women and 89 treatment cycles were evaluated. The patients were assigned to group 1 (amenorrhea, low FSH and LH, and no evidence of endogenous estrogens, as indicated by lack of withdrawal bleeding after medroxyprogesterone acetate) or group 2 (amenorrhea, with normal gonadotropins and evidence of endogenous estrogens by progestin withdrawal bleeding). Three patients underwent HMG therapy for inadequate luteal phase; none of them became pregnant. All patients from group 1 became pregnant (8/8), and 45% (5/11) of patients from group 2 became pregnant. The difference in pregnancy rates is significant (P less than .05). The cumulative pregnancy rate for each group was calculated by the life table method. All the cases of multiple gestation (three) came from group 1, and all the cases of ovarian hyperstimulation (five) came from group 2. In summary, in our experience patients from group 1 had a higher pregnancy rate and a greater incidence of multiple gestation than patients in group 2, who had a greater chance of developing ovarian hyperstimulation.     

X-chromosome abnormalities in women with premature ovarian failure.

OBJECTIVE: To evaluate the significance of X-chromosome abnormalities identified in a series of women with premature ovarian failure (POF). STUDY DESIGN: Karyotypes were reviewed for all women referred to our cytogenetic laboratory over a five-year interval with the diagnosis of POF. Thirty women aged less than 40 with unexplained secondary amenorrhea and elevated follicle-stimulating hormone were included. RESULTS: Of the 30 patients, 26 had a normal karyotype and 4 showed the following X-chromosome abnormalities: 46,Xi(Xq), 45,X/46,XX mosaic, 46,X,der(X)t(X;Y)(q28;q12) mat and 46,X,t(X;5)(q22;q11.2) mat. In the two families with familial translocations, carrier females within each family showed considerable variability in age at onset of menopause. CONCLUSION: Both familial and nonfamilial X-chromosome abnormalities can be identified in women with POF. Cytogenetic studies should not be limited to those patients with very-early-onset POF.     

Acute pulmonary edema occurred during tocolytic treatment using nicardipine in a twin pregnancy. Report of three cases

We report three cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in twin pregnancy patients with no previous heart problems. The three patients were admitted into our unit on account of the risk of premature birth after 29 to 32 weeks of amenorrhea. The treatment by intravenous tocolysis using nicardipine combined with glucocorticoids therapy had been undertaken in the previous maternity ward. The three patients presented symptoms of acute dyspnea 48 hours after the beginning of the treatment. Paraclinical examinations eliminated the diagnosis of pulmonary embolism. The patients'condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. There are currently few studies proving the benefits of nicardipine in tocolysis treatment. Few similar cases of acute pulmonary edema have been noted in twin pregnancy patients treated with nicardipine. Haemodynamic modifications specific to twin pregnancy, intravenous hydratation and glucocorticoid maturation may explain a part of this complication. Therefore, it is appropriated to limit the use of intravenous nicardipine in the sole indication of tocolysis in twin pregnancy, and to prefer the use of nifedipine and atosiban, that have proven their effectiveness in this indication.     

Subclavian deep vein thrombosis associated with the use of recombinant follicle-stimulating hormone (Gonal-F) complicating mild ovarian hyperstimulation syndrome

OBJECTIVE: To describe two cases of subclavian deep vein thrombosis (DVT) associated with the use of recombinant gonadotropins and mild ovarian hyperstimulation syndrome (OHSS) and review the literature associated with this condition. DESIGN: Retrospective study (case report). SETTING: Tertiary academic IVF program. PATIENT(s): Two women undergoing IVF with intracytoplasmic sperm injection due to male factor infertility. INTERVENTION(s): Ovaluation induction with recombinant FSH, IVF, and therapeutic heparinization. MAIN OUTCOME MEASURE(s): Coagulation studies, resolution of DVT, delivery at term. RESULT(s): Mild OHSS with left subclavian thrombosis occurred in two patients. Laboratory evaluation revealed normal protein C, protein S, antinuclear antibodies (ANA), and absence of antiphospholipid (APA) and anticardiolipin antibodies (ACA). Antithrombin III levels and coagulation studies were also within normal limits. Both patients tested negative for a factor V Leiden mutation and delivered healthy infants at term. CONCLUSION(s): Arm swelling associated with the use of gonadotropins during controlled ovarian hyperstimulation should be promptly evaluated and treated. Subclavian vein thrombosis is a rare complication of ovulation induction, and the possibility that recombinant gonadotropins increase the risk for this complication should be further studied.     

Serum 17beta-estradiol. Index of follicular maturation during gonadotropin therapy

Thirteen patients with hypogonadotropic hypogonadism were treated with human menopausal gonadotropins (hMG) and human chorionic gonadotropin (hCG) to induce ovulation. Daily serum 17beta-estradiol (E2) assays were used to monitor the ovarian response to HMG. Apparent ovulation, documented by basal body temperatures, occurred in 41 of 53 hMG-hCG treatment cycles. Thirteen pregnancies occurred in 8 of the 13 patients. One twin pregnancy resulted. The hyperstimulation syndrome did not occur. Our data indicate that an optimal pregnancy rate with a minimum risk of hyperstimulation can be achieved when ovulation is induced 24 hours after the preovulatory serum E2 concentration has reached 500 to 900 pg/ml. Ovulation is induced by administering 10,000 IU and 5000 IU hCG on successive days. In addition, we now routinely give two or three injections of 2500 IU hCG at subsequent 3- to 4-day intervals to support the corpus luteum.