Maria Eugenia Escobar

Screening of FSH receptor gene in Argentine women with premature ovarian failure (POF).

Diverse mutations in FSH-receptor (FSHR) gene have been described as possible cause of premature ovarian failure (POF). To investigate the presence of mutations and/or polymorphisms in FSHR gene, DNA from 20 POF, 5 of which were diagnosed as resistant ovary syndrome (ROS), and from 44 controls was isolated from peripheral lymphocytes. The complete coding sequence was analysed by PCR followed by SSCP, direct sequencing or restriction enzyme analysis. No mutations in FSHR gene were identified in the patients studied. The two already described polymorphisms in exon 10, A919G and A2039G, cosegregated in all the homozygous individuals, indicating that FSHR presents two isoforms: Ala307-Ser680 and Thr307-Asn680. OR results suggest that the 919G-2039G allelic variant or the homozygous genotype is not associated to disease risk. In addition, a heterozygous substitution T1022C (Val341Ala) was found in two control subjects. We suggest that mutations in FSHR gene are rare in women with POF in Argentine. Presence of a particular FSHR isoform does not appear to be associated with this disease.

Evaluation of gonadal function following long-term treatment for acute lymphoblastic leukemia in girls

Twenty-four girls were studied following long-term treatment (mean: 50 months) for acute lymphoblastic leukemia; 14 were prepubertal and 10 pubertal. Follow-up during endocrine studies ranged from 2 months to 6.7 years (mean: 2.3 years). Five of 14 prepubertal patients started clinical pubertal development at a normal age and were reevaluated during puberty, increasing the pubertal group to 15 patients. Thirteen of 15 pubertal patients had received cranial radiotherapy. Ten of 15 pubertal patients started menses during the endocrine study. Although age of menarche was normal, in nine patients it was below the normal mean. Except for the remaining patient, all had received cranial cobalt therapy. In 6 of 19 patients bone age was significantly accelerated. Serum gonadotrophin response to LH-RH was normal in 13 prepubertal patients and in 10 pubertal patients. In 3 of 10 pubertal patients follicle-stimulating hormone (FSH) values were temporarily elevated. Only one pubertal patient had oligoamenorrhea. Five patients were studied by measuring serum progesterone on days 19-22 of the cycle to determine corpus luteum function. Three of them showed progesterone levels compatible with adequate corpus luteum function (6, 19, and 12 ng/ml, respectively) and two presented low progesterone levels (2 ng/ml), probably because of their short gynecological age (0.24 and 0.3 years, respectively). This study suggests that neither the disease nor the long-term antileukemia therapy seems to injure gonadal function in girls. A tendency to early sexual development was observed, which may be related to cranial cobalt therapy.

Long-term endocrine sequelae after surgery, radiotherapy, and chemotherapy in children with medulloblastoma

Thirteen children with medulloblastoma, were studied after 2 to 62 months off radiotherapy and chemotherapy with methotrexate and BCNU. Ages at time of study ranged from 2.3 to 15.7 years. Eleven patients, followed for a mean of 22 months, showed a significant decrease of height score, whereas nine patients had deficient growth hormone (GH) response to provocative tests. Clinical pubertal progression was normal in all patients, and three of five girls with advanced pubertal development had menarche. No evidences of gonadotropin disturbances were found in five patients whereas seven had raised basal folliclestimulating hormone (FSH) level or FSH response to luteinizing hormone‐releasing hormone (LH‐RH). Abnormalities in thyrotrophin (TSH) secretion were found in 9 of 13 patients. This study shows that poor growth and GH deficiency were frequent in our patients. The high frequency of thyroid disturbances observed point out the need of evaluating thyroid function for adequate replacement therapy. Perhaps modification of adjuvant chemotherapy in the future can diminish drug‐induced gonadal damage. Cancer 59:801‐806, 1987.

Acute effects of testosterone infusion on the serum luteinizing hormone profile in eumenorrheic and polycystic ovary syndrome adolescents.

CONTEXT Little is known about the neuroendocrine effects of androgens on the GnRH-LH unit in females. OBJECTIVE Our objective was to evaluate androgen negative feedback on the GnRH-LH axis in eumenorrheic and polycystic ovary syndrome (PCOS) adolescents. DESIGN AND SETTING We conducted a prospective, longitudinal, randomized, double-blind study at a pediatric endocrinology clinical research center. PARTICIPANTS Seven nonobese PCOS adolescents and seven matched controls (C) were studied in the early follicular phase of three consecutive menstrual cycles or in three consecutive months. INTERVENTION Pulsatile LH release was determined during saline [baseline (B)] and constant testosterone (T) infusions: low dose (T-LD) 0.75 and high dose (T-HD) 2.5 mg/12 h iv. Blood samples were drawn every 20 min overnight. MAIN OUTCOME MEASURES LH (immunofluorometric assay) and T (electrochemiluminescence immunoassay) were determined at B, and during both T-LD and T-HD. LH profiles were analyzed by deconvolution and approximate entropy analyses. RESULTS On T-LD, C and PCOS serum T levels increased 2- to 3-fold vs. B. On T-HD, T values doubled in both groups vs. T-LD. Controls on T-LD had greater 12-h pulsatile LH secretion rate (P < 0.05 vs. B) and on T-HD had lower mean, pulsatile, basal LH release and LH approximate entropy (vs. B, P < 0.05). PCOS did not respond to T-LD. High-dose T did not alter mean LH in PCOS but increased pulsatile and reduced basal LH secretion. CONCLUSIONS PCOS adolescents have impaired suppression of pulsatile LH secretion rate consistent with reduced androgen negative feedback. Attenuation of T feedback in nonobese adolescents with PCOS extends the pathophysiology of this syndrome.

Spontaneous Ovarian Hyperstimulation Syndrome Caused by a Follicle-Stimulating Hormone-Secreting Pituitary Macroadenoma in an Early Pubertal Girl

Gonadotroph adenomas are difficult to diagnose since they usually show as nonsecreting tumors or produce biologically inactive hormones with no clinical effects and classically grow silent until neurological symptoms appear. Presentation with bilateral ovarian masses and ovarian hyperstimulation has been described in fertile years. Gonadotroph adenomas are extremely infrequent in children. We report a 13-year-old postmenarcheal girl referred to our hospital with 6 months of amenorrhea, abdominal palpable mass presumptive of bilateral ovarian tumors. The patient had Tanner IV breast development and a large abdominal mass occupying the whole low hemiabdomen. Laboratory evaluation revealed high estradiol levels with suppressed luteinizing hormone and inappropriately high follicle-stimulating hormone (FSH) levels. Pelvic ultrasound showed enlarged ovaries containing multiple giant cysts. An MRI revealed a pituitary macroadenoma. Transsphenoidal resection of the adenoma was performed with an uneventful postoperative course. Immunohistologic examination only showed staining for FSH, thus confirming pituitary secreting FSH adenoma. Hormonal laboratory levels normalized and ovarian masses showed marked involution 1 month after surgery. Three months later the MRI showed tumor disappearance. Conclusion: The presence of bilateral ovarian tumors requires a careful endocrine and neurological evaluation to exclude the presence of an FSH-producing tumor in order to avoid unnecessary ovarian surgery.

Acceleration of luteinizing hormone pulse frequency in adolescent girls with a history of central precocious puberty with versus without hyperandrogenism

Some adolescents with a history of idiopathic central precocious puberty (ICPP) develop hyperandrogenism. Hypothesis: Luteinizing hormone (LH) hypersecretion could be a common mechanism underlying ICPP and polycystic ovary syndrome. Aim: To explore the GnRH-LH axis in those patients. Design: To compare overnight LH secretion in 7 healthy adolescents (CG) with that in patients with prior ICPP [5 with (CPPA) and 7 without (CPPB) hyperandrogenism]. To analyze daytime LH secretion in those patients. Methods: LH secretion was quantified by immunofluorometry and deconvolution analysis. Results: Nighttime mean LH (international units/liter) was higher in CPPA (6.9 ± 1.5) than in CPPB (3.2 ± 0.4, p < 0.05) and CG (2.9 ± 0.4, p < 0.01). Deconvolution analysis revealed a greater nighttime LH frequency (pulses/hour) both in CPPA (0.91 ± 0.06, p < 0.01) and CPPB (0.74 ± 0.02, p < 0.05) than in CG (0.45 ± 0.07). CPPA patients maintained a higher frequency than CPPB. Pulsatile LH production was greater in CPPA than in CG (50 ± 12 vs. 18 ± 3 IU/l/day, p < 0.01). Daytime mass of LH released per burst and pulsatile production rate were significantly greater in CPPA than in CPPB patients. Conclusions: Hyperandrogenic adolescents with prior ICPP show increased pulsatile LH secretion. Augmentation of LH pulsatility may predispose to or cause hyperandrogenism in some adolescents with a history of precocious puberty.

High diagnostic accuracy of subcutaneous Triptorelin test compared with GnRH test for diagnosing central precocious puberty in girls

The GnRH test is the gold standard to confirm the diagnosis of central precocious puberty (CPP); however, this compound is not always readily available. Diagnostic accuracy of subcutaneous GnRH analogues tests compared to classical GnRH test has not been reported.

Assessment of Estradiol Response after Depot Triptorelin Administration in Girls with Central Precocious Puberty.

Background: Estradiol at baseline or after a classical gonadotropin-releasing hormone test did not reflect ovarian steroidogenesis in central precocious puberty (CPP) girls. Aims: To evaluate estradiol response to depot triptorelin, both at start and during therapy to determine how active ovarian steroidogenesis is at pubertal stage and under therapy. Methods: A prospective study was performed in 43 CPP girls. Serum luteinizing hormone and follicle-stimulating hormone at 3 h (LH-3h, FSH-3h) and estradiol at 24 h (E2-24h) after injection of depot triptorelin 3.75 mg were measured, at first dose and at 3, 6, 12, 18 and 24 months of treatment. Results: E2-24h after depot triptorelin was >100 pg/ml after the first dose. Estradiol response (E2-24h) fell to levels <14 pg/ml in 78 out of 82 follow-up visits along 2 years of therapy. Concomitantly, LH-3h and FSH-3h were <4.0 and <6.3 IU/l, respectively. In 4 patients with inadequate treatment, E2-24h, LH-3h and FSH-3h rose to pubertal values similar to those observed at first dose. Conclusion: Estradiol (<14 pg/ml) assessment 24 h after depot triptorelin administration is a reliable and simple manner to confirm ovarian suppression in CPP girls during treatment.

Bone age at discontinuation of medroxyprogesterone acetate therapy in girls with precocious puberty: effect on final height.

To determine the final height of patients with precocious puberty treated with medroxyprogesterone acetate (MPA; 150 mg every week) for a period > 1 year (mean +/- SD = 3.24 +/- 1.85 years), data from a group of 26 girls were analyzed. The attained final height was 155.6 +/- 8.06 cm (-1.1 SD of the normal population). In a group of 8 untreated girls with precocious puberty, adult height was 149.2 +/- 5.07 (-2.16 SD, p < 0.02). In 9 patients in whom treatment was stopped at a bone age < or = 12 years, final height was 159.2 +/- 10.05 cm, while in 16 girls who had a bone age > 12 years at the end of treatment, the final height was 153.03 +/- 6.28 cm. Our data demonstrate the effectiveness of MPA treatment on ultimate height. The better height observed in those patients who stopped treatment with a bone age < 12 years suggests the advantage of discontinuing therapy before reaching a more advanced degree of skeletal maturation.

Allele-Specific Amplification (AS-PCR) for Point Mutation Screening of G Protein α-Subunit (Gsα) in McCune-Albright Syndrome (MAS)

Allele-Specific Amplification (AS-PCR) for Point Mutation Screening of G Protein α-Subunit (Gsα) in McCune-Albright Syndrome (MAS)