SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action.

Objective: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. Participants: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. Conclusions: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented. (J Clin Endocrinol Metab 96: 273–288, 2011)

Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.

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Advances in the treatment of prolactinomas.

Publisher Summary This chapter presents an overview of the regulation of the mammalian corpus luteum (CL) The CL is an ovarian follicle in which the rapid regression—that is otherwise the fate of all postovulatory follicles—is temporarily arrested In the mammalian CL, progesterone secretion goes hand in hand with the postponement of regression It is fairly certain that reptilian CL also secretes progesterone The mammalian CL is formed during the period around ovulation by a transformation of the cells lining the cavity of the follicle Luteinization affects the granulosa cells in all species It involves an enormous enlargement of the cell with a great increase in the nucleus–cytoplasm ratio and the formation of a very distinct cell wall, the development of an extensive capillary network enmeshing all the cells, a marked proliferation of the endoplasmic reticulum, and its transformation from a predominantly rough to a predominantly smooth type, a marked proliferation of the mitochondria from a small round or rod shape type with lamelliform cristae into larger and more varied shapes with tubular and villiform cristae, and an increase in the complexity of the Golgi apparatus The CLs activity differs most from that of the follicle in how much rather than in what kinds of steroid it makes The principal change is a striking increase in progesterone secretion, accompanied by a variable, but severe fall or even loss of the capacity for estrogen and androgen secretion

The Regulation of the Mammalian Corpus Luteum

Summary
Background The discovery of somatostatin (SST) and the synthesis of a variety of analogues constituted a major therapeutic advance in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours (GEP-NETs). They currently provide the most efficient treatment to achieve symptomatic relief and have recently been demonstrated to inhibit tumour growth.

Aim  To review 35 years of experience regarding the clinical application and efficacy of SST analogues.

Methods  The PubMed database (1972–2009) was searched using somatostatin as a search term with combinations of terms including ‘treatment’; ‘neuroendocrine’; ‘carcinoid’; ‘tumor’; ‘octreotide’; ‘lanreotide’ and ‘pasireotide’.

Results  In a review of 15 studies including 481 patients, the slow-release formulations Sandostatin LAR and Somatuline SR/Autogel achieved symptomatic relief in 74.2% (61.9–92.8%) and 67.5% (40.0–100%), biochemical response in 51.4% (31.5–100%) and 39.0% (17.9–58%), and tumour response in 69.8% (47.0–87.5%) and 64.4% (48.0–87.0%) respectively. Novel SST analogues like SOM230 (pasireotide) that exhibit pan SST receptor activity and analogues with high affinity to specific somatostatin receptor (sstr) subtypes may further advance the field, but efficacy studies are lacking.

Conclusion  As more precise understanding of NET cell biology evolves and molecular biological tools advance, more accurate identification of individual tumours sstr profile will probably facilitate a more precise delineation of SST analogue treatment.

Aliment Pharmacol Ther 31, 169–188

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2009.04174.x

Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours.

An unexpected 20-week-old pregnancy was found in a young acromegalic who had been treated with 10 mg bromocriptine/day for 10 months. The drug was continued throughout the period of gestation. No growth of the pituitary adenoma was noticed. The intrauterine development of the fetus was normal. Bromocriptine therapy had no discernible effect on the expected patterns of secretion of placental hormones, but inhibited completely the increase of PRL in the serum of the mother. Maternal plasma GH concentrations were very high in spite of the treatment and progressively declined after delivery. The plasma GH level was normal in the child, but PRL was very low at birth and increased in the following days. The expected high PRL concentration was found in the amniotic fluid. This case study suggests that bromocriptine crosses the human placenta and affects the fetal pituitary, maternal GH does not influence fetal or amniotic GH, and amniotic fluid PRL correlates poorly with either maternal or fetal blood levels and...

A Pregnancy in an Acromegalic Woman during Bromocriptine Treatment: Effects on Growth Hormone and Prolactin in the Maternal, Fetal, and Amniotic Compartments*

The acute GH inhibitory effects of 50 ⁄g SMS 201–995, a somatostatin analog, and 2.5 mg bromocriptine were compared in 17 acromegalic patients. SMS 201–995 suppressed plasma GH levels after 2—6 h to 5 μg⁄liter or less in 10 of these 17 patients, while bromocriptine did the same in only 5 of them. There was much variation in the responsiveness to both drugs in these patients, but the GH–lowering effect of 50 ng SMS 2017– 995 was significantly greater than that of 2.5 mg bromocriptine. SMS 201–995 and bromocriptine togethersignificantly suppressed plasma GH levels in 2 of 3 acromegalic patients who were insensitive to both compounds when tested separately. We conclude that most acromegalic patients respond better toSMS 201–995, while a few patients are more sensitive to the GH–lowering effect of bromocriptine. In addition, the combination of SMS 201–995 and bromocriptine can be of value in a fewacromegalic patients who do not respond to either drug alone. (J Clin Endocrinol Metab 63:16,1986)

A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs.

Pattern of sexual steroids, prolactin, and gonadotropic hormones during prolactin inhibition in normally cycling women.

The somatostatin analogue SMS 201-995 has recently been shown to be effective in suppressing GH secretion in most acromegalic patients. In the present study it was investigated whether PRL release in prolactinoma and acromegalic patients might also be sensitive to SMS 201-995 and whether co-secretion of PRL in acromegaly plays a role in determining the sensitivity of GH secretion to SMS 201-995. The s.c. administration of 50 micrograms SMS 201-995 did not affect high plasma PRL levels in four microprolactinoma patients. Therapy of one of these patients for 3 d with 50 micrograms three times a day also did not affect PRL levels. The single administration of 50 micrograms SMS 201-995 in 22 acromegalic patients lowered plasma GH levels for 2-6 h to less than 5 micrograms/l in 14 patients and to less than 50% of control values in 16 patients. In 18 of these 22 patients the immunohistochemical picture of the pituitary tumour was known. Eleven patients had pure GH-containing tumours and in seven patients there were mixed GH/PRL-containing tumours. In two of these latter patients there was evidence for GH and PRL being secreted by the same tumour cells. The sensitivity of GH secretion to SMS 201-995 did not differ between the patients with pure GH or mixed GH/PRL-containing adenomas. Plasma PRL levels were not affected by SMS 201-995 in the patients with pure GH-secreting tumours, but were significantly suppressed in four of the seven patients with mixed GH/PRL containing tumours. Chronic treatment for 16 weeks of one patient with a mixed GH/PRL-containing tumour with SMS 201-995 (100 micrograms three times a day) resulted in normalization of both the increased GH and PRL levels. It is concluded that SMS 201-995 does not affect tumorous PRL secretion in patients with pure prolactinomas. In acromegalic patients with mixed GH/PRL-containing tumours PRL secretion in some patients is sensitive to SMS 201-995, making these patients good candidates for chronic treatment with the analogue. The simultaneous presence of PRL in the GH-secreting pituitary tumour or the presence of hyperprolactinaemia in acromegalics does not play a role in the sensitivity of GH secretion to the somatostatin analogue.

The sensitivity of growth hormone and prolactin secretion to the somatostatin analogue SMS 201-995 in patients with prolactinomas and acromegaly.

The effect of a new soluble ester of 1-5 hydroxytryptophan (1-5 HTP, Ro 3-5940, 200 mg infusion) on prolactin (PRL) and growth hormone (GH) release was tested in 11 young, healthy subjects (6 men, 5 women). To minimize side-effects, peripheral decarboxylase inhibition was achieved with benserazide (Ro 4-4602.) PRL increased significantly (P less than 0.01) after benserazide alone in all subjects. A further significant increase (P less than 0.01) of PRL plasma levels occurred only in women up to 90 min after the infusion of 1-5 HTP was discontinued. Benserazide administration had no effect of basal GH levels, but a significant increase of GH release (P less than 0.01) was noticed 30-120 min after the end of 1-5 HTP infusion in both men and women. The mean peak value of GH plasma levels after 1-5 HTP administration was 32.0 +/- 8.8 ng/ml. It was postulated that benserazide penetrated at the level of the pituitary, decreasing the synthesis of dopamine and consequently reducing its known inhibitory effect on PRL release. The PRL increase (statistically significant only in women), as well as the release of GH after 1-5 HTP infusion, was considered as further evidence for stimulatory serotoninergic control of both PRL and GH secretion.

E. del Pozo

Papers

A Pregnancy in an Acromegalic Woman during Bromocriptine Treatment: Effects on Growth Hormone and Prolactin in the Maternal, Fetal, and Amniotic Compartments*

A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs.

Pattern of sexual steroids, prolactin, and gonadotropic hormones during prolactin inhibition in normally cycling women.

The sensitivity of growth hormone and prolactin secretion to the somatostatin analogue SMS 201-995 in patients with prolactinomas and acromegaly.

Effect of 1-5 hydroxytryptophan infusion on growth hormone and prolactin secretion in man.