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Rogerio Silicani Ribeiro and Julio Abucham

Context

Persistence of hypogonadism is common in male patients with prolactinomas under dopamine agonist (DA) treatment. Conventional therapy with testosterone causes undesirable fluctuations in serum testosterone levels and inhibition of spermatogenesis.

Objective

To evaluate the use of clomiphene as a treatment for persistent hypogonadism in males with prolactinomas.

Design

Open label, single-arm, prospective trial.

Patients

Fourteen adult hypogonadal males (testosterone <300 ng/dl and low/normal LH) with prolactinomas on DA, including seven with high prolactin (range: 29–1255 μg/l; median: 101 μg/l) despite maximal doses of DA.

Intervention

Clomiphene (50 mg/day orally) for 12 weeks.

Measures

Testosterone, estradiol, LH, FSH, and prolactin were measured before and 10 days, 4, 8, and 12 weeks after clomiphene. Erectile function, sperm analysis, body composition, and metabolic profiles were evaluated before and after clomiphene.

Results

Ten patients (71%), five hyperprolactinemic and two normoprolactinemic, responded to clomiphene (testosterone >300 ng/dl). Testosterone levels increased from 201±22 to 457±37 ng/dl, 436±52, and 440±47 ng/dl at 4, 8, and 12 weeks respectively (0.001<P<0.01). Estradiol increased significantly and peaked at 12 weeks. LH increased from 1.7±0.4 to 6.2±2.0 IU/l, 4.5±0.7, and 4.6±0.7 IU/l at 4, 8, and 12 weeks respectively (0.001<P<0.05). FSH levels increased in a similar fashion. Prolactin levels remained unchanged. Erectile function improved (P<0.05) and sperm motility increased (P<0.05) in all six patients with asthenospermia before clomiphene.

Conclusions

Clomiphene restores normal testosterone levels and improves sperm motility in most male patients with prolactinomas and persistent hypogonadism under DA therapy. Recovery of gonadal function by clomiphene is independent of prolactin levels.

Free access

Julio Abucham, Marcello D Bronstein and Monike L Dias

Although fertility is frequently impaired in women with acromegaly, pregnancy is apparently becoming more common due to improvement in acromegaly treatment as well as in fertility therapy. As a result, several studies on pregnancy in patients with acromegaly have been published in recent years adding new and relevant information to the preexisting literature. Also, new GH assays with selective specificities and the knowledge of the expression of the various GH genes have allowed a better understanding of somatotrophic axis function during pregnancy. In this review, we show that pregnancy in women with acromegaly is generally safe, usually with tumoral and hormonal stability. Although the paucity of data limits evidence-based recommendations for preconception counseling and pregnancy surveillance, controlling tumor size and hormonal activity before pregnancy is highly recommended to ensure better outcomes, and surgical control should be attempted when feasible. Treatment interruption at pregnancy confirmation has also proven to be safe, as drugs are not formally allowed to be used during pregnancy. Drug exposure (somatostatin analogs) during early or whole pregnancy might increase the chance of a lower birth weight. Aggressive disease is uncommon and may urge individual decisions such as surgery or drug treatment during pregnancy or lactation.

Free access

Rogerio Silicani Ribeiro, Teresa Cristina Vieira and Julio Abucham

Kallmann syndrome (KS) describes the association of isolated hypogonadotropic hypogonadism with hypo/anosmia. A few KS patients may reverse hypogonadism after testosterone withdrawal, a variant known as reversible KS. Herein, we describe the first mutation in KAL1 in a patient with reversible KS and review the literature. The proband was first seen at 22 years complaining of anosmia and lack of puberty. His brother had puberty at 30 years and a maternal granduncle had anosmia and delayed puberty. On physical examination, he was P2G1, testes were 3 ml and bone age was 14 years. During 20 years of irregular testosterone replacement, he developed secondary sexual characteristics and testicular enlargement. At the age of 41 years, after stopping testosterone replacement for 5 months, his testes were 15 ml, serum testosterone, LH, and FSH responses to GnRH were normal, and his wife was pregnant. The molecular study revealed a cytosine insertion in exon 2 of KAL1, generating a frameshift at codon 75 and a premature stop at codon 85. The expected gene product is a truncated peptide with 85 of the 610 amino acids present in the wild-type protein. Fourteen cases of reversible KS have been described but the genotype was only studied in a single case showing a heterozygous fibroblast growth factor receptor type 1 (FGFR1) mutation. Considering the low prevalence of mutations in KAL1 or FGFR1 in KS, it is possible that these genotypes are more prevalent in reversible KS than in other KS patients, but additional studies are necessary to confirm this hypothesis.

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Edelweiss F Tavares, Ivaldir S Dalbosco, Julio Abucham and Ewaldo MK Russo

Tavares EF, Dalbosco IS, Abucham J, Russo EMK. True insulin and intact proinsulin levels in acromegalic patients. Eur J Endocrinol 1996;134:549–53. ISSN 0804–4643

To determine whether proinsulin (PI) contributes significantly to the immunoreactive insulin (IRI) concentrations in acromegalics, we measure PI, "true insulin" and IRI in a group of acromegalics compared with a control group. Serum PI was determined by the immunofluroimetric assay (IFMA). Insulin was also determined by an IFMA that measures true insulin and by a radioimmunoassay (RIA). We performed an oral glucose tolerance test (OGTT) in a total group of 46 subjects: 10 controls with normal OGTT and body mass index <25 kg/m2 (control group I), 10 controls with normal OGTT and body mass index > 25 kg/m2 (control group II), 15 patients with active acromegaly and normal OGTT and 11 patients with active acromegaly and IGT. Plasma glucose, serum GH, insulin and proinsulin were measured in all OGTT samples. Basal levels of insulin-like growth factor I (IGF-I) were measured in acromegalics. Mean body mass index in acromegalics with normal and impaired glucose tolerance were significantly higher compared with control group I and similar when compared with control group II. Proinsulin increased during OGTT in acromegalics with impaired glucose tolerance compared to control group I, and only fasting proinsulin compared to control group II. In normal OGTT acromegalics, only fasting proinsulin was increased. The RIA insulin during OGTT was significantly higher for both acromegalic groups compared to control group I and only at fasting when compared with control group II. This difference was not evident when insulin was measured by IFMA. These results suggest that in acromegalics, hyperinsulinism measured by RIA was at least in part due to hyperproinsulinism.

Ewaldo MK Russo, PO Box 20266, CEP 04034-970, Sáo Paulo, SP, Brazil

Free access

Monike Dias, Cesar Boguszewski, Monica Gadelha, Leandro Kasuki, Nina Musolino, Jose G H Vieira and Julio Abucham

Context and objective

The interaction between pregnancy and acromegaly has been studied only retrospectively. We used prospective data to assess those interactions.

Design

Prospective, interventional, multicentric study.

Patients

Ten pregnancies in eight acromegalic patients were included according to the following criteria: previous diagnosis of acromegaly; and active acromegaly before pregnancy. Sellar magnetic resonance image (MRI), GH, and IGF1 measurements were carried out before pregnancy. The exclusion criterion was radiotherapy.

Intervention

Withdrawal of pharmacological treatment (octreotide and/or cabergoline and/or pegvisomant) following pregnancy diagnosis.

Main outcome measures

Clinical/biochemical evaluations throughout pregnancy/puerperium and sellar MRI after delivery; and GH and IGF1 measurements before pregnancy. GH was measured by an interference-free IFMA assay during pregnancy and IGF1 by measured by Immulite 2000 assay in patients and 64 control pregnancies.

Results

No tumor growth was observed. Nine deliveries were at term and one at 35 weeks (preeclampsia). All newborns were healthy. Mean IGF1 levels before and during pregnancy were similar, but increased significantly during puerperium. As IGF1 in controls increased after midgestation, the prevalence of controlled IGF1 rose significantly from 2/10 (<20 weeks) to 9/10 (>30 weeks). Diabetes mellitus and hypertension/preeclampsia developed in one patient in each group; both complications were nonsignificantly (P=0.06) associated with IGF1 >1.3 ULN before pregnancy.

Conclusions

Acromegaly control usually improved and tumor growth was not stimulated during pregnancy in spite of withdrawal of drug treatment. Drug treatment can be discontinued in most patients. Uncontrolled disease before pregnancy may pose a higher risk for diabetes and hypertension.

Free access

Fabio Casanova Doin, Mariana Rosa-Borges, Manoel R A Martins, Valdir A Moisés and Julio Abucham

Objective

The diagnosis of subclinical central hypothyroidism in hypothalamic–pituitary patients cannot be established by serum markers of thyroid hormone action. Myocardial function by echocardiography has been shown to reflect thyroid hormone action in primary thyroid dysfunction. We evaluated the performance of echocardiography in diagnosing subclinical central hypothyroidism.

Design

Cross-sectional and before and after.

Methods

Echocardiography and serum thyroid hormones were assessed in overt primary (n=20) and central (n=10) hypothyroidism, subclinical primary hypothyroidism (n=10), hypothalamic–pituitary disease with normal free thyroxine (FT4; n=25), and controls (n=28). Receiver operating characteristic (ROC) curves were generated using overt hypothyroidism patients and selected cut-off values were applied to detect both primary and central subclinical hypothyroidism. After levothyroxine (l-T4) intervention, patients were echocardiographically reevaluated at predefined targets: normal thyrotropin (TSH) in primary hypothyroidism, normal FT4 in overt central hypothyroidism, and higher than pretreatment FT4 in echo-defined subclinical central hypothyroidism.

Results

Parameters with highest areas under the ROC curves (area under the curve (AUC) ≥0.94) were as follows: isovolumic contraction time (ICT), ICT/ejection time (ET), and myocardial performance index. Highest diagnostic accuracy (93%) was obtained when at least one parameter was increased (positive and negative predictive values: 93%). Hypothyroidism was echocardiographically diagnosed in eight of ten patients with subclinical primary hypothyroidism and in 14 of 25 patients (56%) with hypothalamic–pituitary disease and normal serum FT4. Echocardiographic abnormalities improved significantly after l-T4 and correlated (0.05<P<0.001) with changes in FT4 (−0.62<r<−0.55) and TSH (0.63<r<0.68) in primary hypothyroidism and with FT4 in central hypothyroidism (−0.72<r<−0.50).

Conclusion

Echocardiography can be useful in diagnosing subclinical central hypothyroidism in patients with hypothalamic–pituitary disease.