Current pharmacotherapy for acromegaly: a review

Acromegaly is associated with considerable morbidity and excess mortality; however, after effective treatment, both morbidity and mortality risks improve. Growth hormone excess in acromegaly can be controlled in many patients by pharmacotherapy alone, and with a combination of transsphenoidal surgery and pharmacotherapy in almost all patients. Since the clinical introduction of pegvisomant, a growth hormone-receptor antagonist, the role of radiotherapy is restricted. This review focuses on the treatment options for acromegaly (e.g., surgery, radiotherapy and pharmacotherapy with the depot preparations of the somatostatin analogues octreotide long-acting release formulation, lanreotide slow-release formulation and lanreotide Autogel, the growth hormone antagonist pegvisomant and the dopamine agonist cabergoline). Pharmacological characteristics of these drugs and the clinical and adverse effects are discussed individually and in relation to the other treatment modalities. The evidence for biochemical goals aimed at during medical treatment and the costs of pharmacotherapy are discussed. A new treatment algorithm is proposed, in which the choice between primary medical treatment and primary surgery is individualised, dependent on adenoma size and extension, patient factors (age, preference for therapy, contraindication for surgery), surgical experience of the centre and octreotide sensitivity of the adenoma. The high cost of lifelong medical treatment, especially of pegvisomant, must be weighed against the cost of a single surgical procedure.     

Treatment strategies for acromegaly

Acromegaly is a chronic debilitating disorder caused by a growth hormone (GH)-producing pituitary adenoma. Active acromegaly is associated with a two- to fourfold increased mortality risk, mainly from cardiovascular disease. Transsphenoidal surgery is considered as the treatment of choice because of the rapidity of cure and normalisation of survival. Secondary treatment modalities are radiotherapy and medical treatment, and are important because surgery in the best hands cures only approximately 60% in long-term studies. Medical treatment with slow-release formulations of somatostatin are now widely used, also as primary treatment, and appear to be safe and effective in 50-60% of the patients. However, no data on mortality risk with these drugs is available. Recently, a GH-receptor blocking agent, pegvisomant, was licensed for use in acromegaly and appears to normalise IGF-1 in almost all patients. This article examines the pathophysiology of acromegaly, currently used medicines and their safety and efficacy, and the new drugs that are in development.     

Identification of structural mutations in the fifth domain of apolipoprotein H (beta 2-glycoprotein I) which affect phospholipid binding

Apolipoprotein H (apoH), also known as beta 2-glycoprotein-I, is considered to be a cofactor for the binding of certain antiphospholipid autoantibodies to negatively charged phospholipids. Genetically determined structural abnormalities in the lipid binding domain(s) of apoH can affect its ability to bind lipid and consequently the production of the autoantibodies. In this study we have identified two common structural mutations at codons 316 and 306 in the fifth domain of apoH which rendered apoH unable to bind to negatively charged phosphatidylserine (PS). The missense mutation at codon 316 (TGG --> TCG) replaces Trp316 with Ser316 and disrupts the integrity of four highly conserved hydrophobic amino acids sequence at positions 313-316, which is a potential protein-lipid hydrophobic interaction site. The missense mutation at codon 306 (TGC --> GGC) involves the substitution of Cys306 by Gly306 which causes the disruption of a disulfide bond between Cys281 and Cys306 and affects the normal configuration of the fifth domain of apoH that appears to be critical for clustering positively charged amino acids along with four hydrophobic amino acids sequence. ApoH from the two homozygotes (Ser316/Ser316) and all seven compound heterozygotes (Ser316/Gly306) failed to bind to PS; all heterozygotes at one or the other sites and wild type showed normal PS binding. These data indicate that the fifth domain of apoH harbors the lipid binding region. An estimated 2 million Caucasians in the United States, who are compound heterozygotes for the two mutations, may be precluded from producing apoH-dependent antiphospholipid autoantibodies.      

Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline

Choroideremia (CHM) is an X-linked progressive eye disorder which results from defects in the human Rab escort protein-1 (REP-1) gene. A gene targeting approach was used to disrupt the mouse chm/rep-1 gene. Chimeric males transmitted the mutated gene to their carrier daughters but, surprisingly, these heterozygous females had neither affected male nor carrier female offspring. The targeted rep-1 allele was detectable, however, in male as well as female blastocyst stage embryos isolated from a heterozygous mother. Thus, disruption of the rep-1 gene gives rise to lethality in male embryos; in female embryos it is only lethal if the mutation is of maternal origin. This observation can be explained by preferential inactivation of the paternal X chromosome in murine extraembryonic membranes suggesting that expression of the rep-1 gene is essential in these tissues. In both heterozygous females and chimeras the rep-1 mutation causes photoreceptor cell degeneration. Consequently, conditional rescue of the embryonic lethal phenotype of the rep-1 mutation may provide a faithful mouse model for choroideremia.      

The cost of infertility diagnosis and treatment in Canada in 1995

The objectives of this study were to estimate the direct cost of infertility management, including diagnosis and treatment, in Canada during 1995, and the relative cost per live birth by treatment category. The analysis was based on the following estimates: the prevalence of infertility in Canada in 1995; the volume and distribution of infertility services; and the effectiveness and cost of specific infertility treatments. In 1995 there were approximately 330,000 couples experiencing infertility in Canada. It is estimated that <50% (150,000) sought medical advice or treatment during that year. A total of 13 diagnostic and treatment categories account for nearly all of the treatments received, and these categories form the treatment model. The cost of treatment per live birth ranges from Cdn$650 for clomiphene treatment of unexplained infertility to Cdn$41,000 for in-vitro fertilization. For a hypothetical group of 100 couples, the annual cost of diagnosis and treatment would be Cdn$77,000 and Cdn$200,000 respectively for a total of Cdn$277,000, or an average of Cdn$2770 per couple. After 1 year of treatment, it is expected that 26 of these 100 couples would achieve a live birth. The total annual cost of infertility management in Canada, estimated to be approximately Cdn$415 million, is 0.6% of the annual cost of health care.      

Upper limb thrombosis associated with assisted conception treatment

Three cases of upper limb deep venous thrombosis occurring in association with assisted conception treatment are presented. The accepted argument that lower limb thrombosis occurring in cases of complicated or severe hyperstimulation syndrome represents the likeliest thrombo-embolic disorder in this situation is questioned.      

Mitochondrial DNA deletion in human oocytes and embryos

Mitochondrial DNA (mtDNA) deletions are present in both human oocytes and embryos. It has been found that these tissues contain a mtDNA mutation which is present in high amounts in patients with Kearns-Sayre syndrome (KSS) and progressive external ophthalmoplegia. In the present study, the frequency of this KSS deletion was investigated in human oocytes and embryos. Using a nested primer polymerase chain chian reaction (PCR) strategy, the frequency of the KSS deletion in 74 human oocytes and 137 embryos was found to be 32.8 and 8.0% respectively. Using a 'long PCR-short PCR' nested primer strategy, the frequency of the KSS deletion in 181 human oocytes and 104 embryos was found to be 47.0 and 20.2% respectively. There was no statistical correlation between the age of the patients at the time of oocyte retrieval and the presence of the deleted molecules. There was a statistical difference between the presence of the deleted molecules in oocytes versus embryos using either technique (P < 0.0001). The relevance of these findings to the accumulation of low levels of deleted mtDNA in both oocytes and embryos is discussed in this study.      

Integrin expression in normal and out-of-phase endometria

Integrins have recently been proposed as having a major role in endometrial receptivity. Different patterns of integrin expression have been described during the normal endometrial cycle, and the co- expression of several integrins, mainly alpha1, alpha4 and beta3 has been considered as specific to the 'window of implantation'. In the present study 55 infertile patients underwent two endometrial biopsies during a single menstrual cycle. An early biopsy was done on postovulatory days 6-8, and a late biopsy was performed on postovulatory days 10 to 12. Histological dating as well as immunohistochemical evaluation of alpha1, alpha4, beta1, beta3, beta5, alpha(v)beta3 integrin expression and oestrogen and progesterone receptors were determined in all endometrial biopsies. Oestradiol and progesterone serum concentrations in serum were evaluated on the same days of the endometrial samplings. Nine out of the 55 midluteal biopsies (16.4%) showed out-of-phase endometria, but all biopsies were in phase in the late luteal phase. Differences in integrin expression between in- and out-of-phase biopsies were observed only for alpha(v)beta3 integrin glandular expression during the midluteal phase. Alpha(v)beta3 integrin glandular expression was found in all late luteal phase biopsies. Alpha(v)beta3 expression was closely correlated with histological maturation of the endometrium appearing suddenly at postovulatory day 6-7 and being expressed by all endometria dated as postovulatory day > or = 8, irrespective of midluteal endometrial biopsies being in phase or out of phase. No differences in integrin expression were detected between patients with or without endometriosis or between patients who became spontaneously pregnant and those who did not. In conclusion, further studies are necessary before patterns of integrin expression may offer an alternative to predict uterine receptivity and implantation potential.      

A randomized controlled trial of three low-dose gonadotrophin protocols for unexplained infertility

This randomized controlled trial assessed which of three low-intensity ovulation induction protocols was associated with the highest rate of cycle completion among infertile women undergoing intrauterine insemination (IUI) with their husband's spermatozoa. Sixty-three women aged < or = 42 years with normospermic partners participated in the study. The primary diagnosis of infertility was unexplained in 89% of subjects, endometriosis in 6% and tubal factor in 5%. Women were assigned to three groups according to recombinant FSH dosage: group A received two ampoules (75 IU FSH per ampoule) on cycle day 4, and one ampoule on days 6 and 8 (total four ampoules); group B received two ampoules on days 4, 6 and 8 (total six ampoules); group C received two ampoules on days 4, 6, 8 and 10 (total eight ampoules). Daily ultrasound investigations began on cycle day 9-12 and human chorionic gonadotrophin (HCG) 5000 IU was administered when one or two follicles > or = 18 mm were seen. IUI was scheduled for the next day. HCG was given and/or ovulation shown to have occurred in 88 of 109 cycles attempted (81%) with no differences among the three dose groups. Two singleton pregnancies occurred (2.3% per ovulatory cycle and 1.8% per cycle start). There were no significant differences among the three regimes in terms of cycle parameters, suggesting that an individualized and more intensive approach to ovarian stimulation is necessary for many women with unexplained infertility.