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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0997
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 9 3374-3377
Copyright © 2007 by The Endocrine Society

CLINICAL CASE SEMINAR

Treatment of Acromegaly with Pegvisomant during Pregnancy: Maternal and Fetal Effects

Susan Riddle Brian, Martin Bidlingmaier, Michael P. Wajnrajch, Stuart A. Weinzimer and Silvio E. Inzucchi

Section of Endocrinology (S.R.B., S.E.I.), Yale University School of Medicine, New Haven, Connecticut 06510; Medizinische Klinik-Innenstadt (M.B.), Ludwig-Maximilians Universität, D-80336 Munich, Germany; Endocrine Care (M.P.W.), Pfizer Global Pharmaceuticals, New York, New York 10017; and Department of Pediatrics (S.A.W.), Yale University School of Medicine, New Haven, Connecticut 06520-8064

Address all correspondence and requests for reprints to: Susan Riddle Brian, M.D., Department of Endocrinology, Yale-New Haven Hospital, 85 Hyde Street, New Haven, Connecticut 06512. E-mail: Susan.Brian{at}yale.edu.


   Abstract
Top
 Abstract
Introduction
 Subject and Methods
 Results (Table 1)
 Discussion
 References
 
Objective: Our objective was to describe the first case of the successful use of pegvisomant during pregnancy in a woman with acromegaly.

Design: We present the case of a 26-yr-old female with acromegaly who had failed surgical and subsequent medical therapy but whose disease was well controlled on pegvisomant. She then conceived and was continued on pegvisomant throughout pregnancy. We then collected both maternal and cord blood samples at parturition, and later analyzed her breast milk.

Results: Maternal IGF-I was well controlled during gestation. Fetal GH and IGF-I were within the normal range. Maternal pegvisomant levels were consistent with a 25-mg daily dosage. Fetal pegvisomant levels were minimal and near the range detected in untreated acromegalic patients, likely representing minimal cross-reactivity from endogenous GH or spurious contamination by maternal blood. GH variant levels in the maternal blood and the cord blood were both within the normal ranges. Pegvisomant levels in breast milk were below the lower limit of quantification of the assay and similar to those observed when analyzing breast milk samples from normal mothers in the same assay. Fetal growth parameters were normal; the baby was healthy and showed no adverse signs.

Conclusions: Pegvisomant therapy during gestation was safe and effective in our patient. Transplacental passage of pegvisomant is either absent or minimal, with a concentration highly unlikely to convey any significant pharmacodynamic effects on the fetal GH and IGF-I system. In addition, there is no evidence of substantial secretion of pegvisomant into breast milk.


   Introduction
Top
 Abstract
 Introduction
Subject and Methods
 Results (Table 1)
 Discussion
 References
 
PEGVISOMANT, A GH antagonist, is currently the most effective medical treatment for acromegaly and is used as adjuvant therapy in patients with persistent disease after transsphenoidal surgery. The average age at the diagnosis of acromegaly is 45 yr, and it is occasionally encountered in women in their reproductive years. Typically, these large tumors impair normal gonadotropin secretion, rendering patients infertile. For example, up to 75% of acromegalic women of reproductive age have at least some menstrual irregularities. However, because of improved microsurgical techniques, fertility is sometimes preserved. As a result, active acromegaly in pregnant women may become an increasingly common clinical scenario.

The safety of pegvisomant during pregnancy, particularly in regard to potential fetal effects, is unknown. Pegvisomant is currently labeled as U.S. Food and Drug Administration Category B, with no teratogenic effects seen in animal models. However, binding of pegvisomant to the GH receptor varies between species, and the data from animal models might not be simply extrapolated to humans. There is no information available as to whether pegvisomant traverses the placental circulation, affects the secretion or action of placental GH variant (GHV), or is excreted into breast milk. We present such data from a single patient with active acromegaly in whom pegvisomant was continued throughout gestation and during nursing.


   Subject and Methods
Top
 Abstract
 Introduction
 Subject and Methods
Results (Table 1)
 Discussion
 References
 
Case report

A 26-yr-old woman was diagnosed with acromegaly in 2003, with classical symptoms, including an irregular menstrual pattern, diaphoresis, soft tissue edema, and acral enlargement. Physical examination revealed changes consistent with moderate acromegaly. A random GH level was elevated at 45 ng/ml (45 µg/liter; normal 0–10), with an IGF-I concentration of 1073 ng/ml (139 nmol/liter; normal 114–492 ng/ml). Magnetic resonance imaging revealed a 2-cm pituitary mass with suprasellar extension, but no direct impingement upon the optic chiasm. The patient underwent transsphenoidal resection, and a pituitary adenoma was confirmed on pathological sections, with immunohistochemistry confirming a GH-producing neoplasm. Two months postoperatively, her GH level remained elevated at 11 ng/ml (11 µg/liter), with an IGF-I of 930 ng/ml (121 nmol/liter), and residual tumor was seen on follow-up magnetic resonance imaging. The patient remained symptomatic. Medical therapy was attempted, first with cabergoline up to a dose of 2 mg weekly, and then with octreotide up to 750 µg/d in three divided doses, but without substantive effects on her GH or IGF-I levels. Therapy with pegvisomant was subsequently initiated at a dose of 10 mg daily by sc injection and later titrated to 15 mg/d. The patient’s symptoms quickly abated, including normalization of menstrual function. Physical features of acromegaly regressed markedly, and her IGF-I decreased to 435 ng/ml (56 nmol/liter).

After 6 months of successful therapy, the patient desired conception, and it was decided, after consultation with a high-risk obstetrical specialist, to continue pegvisomant during any forthcoming pregnancy. The patient conceived during the 13th month of pegvisomant therapy. One month after conception, her IGF-I level was 553 ng/ml (71 nmol/liter), and GH was 28.4 ng/ml (28.4 µg/liter), at which time her pegvisomant was increased to 20 mg/d. The next IGF-I level at 3-month gestation was 455 ng/ml (59 nmol/liter), with GH 28.9 ng/ml (28.9 µg/liter), and her dose was increased again to 25 mg/d. At 6-month gestation, the IGF-I was 240 ng/ml (31 nmol/liter), with GH 19.6 ng/ml (19.6 µg/liter), and at 8 months, the IGF-I was 225 ng/ml (29 nmol/liter). The pegvisomant dose was not further altered.

The pregnancy proceeded uneventfully, with normal fetal growth milestones achieved, documented by routine obstetrical ultrasounds throughout the pregnancy. The patient continued to feel well, without any clinical progression of disease, headaches, or alteration in vision. Her random plasma glucose levels were between 98 and 115 mg/dl (5.4–6.3 mmol/liter), with glycosylated hemoglobin levels between 5.6 and 5.8% throughout pregnancy. Her obstetrician elected not to perform a glucose tolerance test.

The patient underwent successful cesarean section at wk 40 for arrested descent after experiencing spontaneous labor. The baby girl measured 8.4 lb (3.8 kg; 75th percentile) and 20.5 in. (52 cm; 75th percentile), with a head circumference of 14 in. (35.5 cm; 75th percentile); APGAR scores were 8 and 9. Examination by a pediatrician was within normal limits. At 6 months of age, the child is healthy, growing well, and achieving normal developmental milestones.

Methods

At parturition, simultaneous maternal and cord blood were obtained to assess GH, IGF-I, placental GHV, and pegvisomant levels. The GH assay used was a sandwich-type fluoroimmunoassay designed to measure GH concentrations without interference from pegvisomant (1). IGF-I was analyzed using the Diagnostic Products Corp. Bierman Immulite 2000 system (Los Angeles, CA). Normative data for this assay, including those for newborns, have been published (2). The GHV assay uses monoclonal antibodies specifically recognizing GHV without cross-reactivity to GH (3). Spiking experiments with pegvisomant showed that the assay exhibited no cross-reactivity up to concentrations of 500,000 ng/ml (500,000 µg/liter). Serum concentrations of pegvisomant were determined by an immunofluorometric sandwich-type assay involving two monoclonal antibodies raised against human GH and retaining high cross-reactivity with pegvisomant (4). The assay involves a 1:100 predilution of samples. Levels of pegvisomant observed under therapy are 100-1000 times higher than circulating concentrations of GH and GHV. As a result, although the antibodies cross-react with GH and GHV, the interference on the pegvisomant assay result is negligible.


   Results (Table 1Go)
Top
 Abstract
 Introduction
 Subject and Methods
 Results (Table 1)
Discussion
 References
 
Maternal IGF-I was well controlled during gestation, whereas maternal GH was elevated, consistent with the recognized response to pegvisomant. Fetal GH and IGF-I were within the normal range. Maternal pegvisomant levels were consistent with a 25-mg daily dosage. Fetal pegvisomant levels [112 ng/ml (112 µg/liter)] were minimal and near the range detected in untreated acromegalic patients [below or around 50 ng/ml (50 µg/liter)], likely representing minimal cross-reactivity from endogenous GH or spurious contamination by maternal blood. Of note, the level was 158-fold lower than that measured in the maternal circulation. We then investigated the GHV levels in the maternal blood and the cord blood, both of which were within the normal ranges; trivial amounts of GHV are frequently seen in cord blood, also probably due to contamination by maternal blood.


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  		TABLE 1. Maternal and cord blood results at parturition

 
Pegvisomant levels in the patient’s breast milk were below the lower limit of quantification [<50 ng/ml (50 µg/liter)] of the assay and similar to those observed when analyzing breast milk samples from normal mothers in the same assay. Breast milk GH concentration was 0.6 ng/ml (0.6 µg/liter), whereas in three breast milk samples from normal healthy mothers, concentration was consistently less than 0.1 ng/ml (0.1 µg/liter).


   Discussion
Top
 Abstract
 Introduction
 Subject and Methods
 Results (Table 1)
 Discussion
References
 
To our knowledge, this the first report of a woman who continued pegvisomant therapy for acromegaly during pregnancy. Chronic suppression of IGF-I was maintained, without the need for dosage adjustment after some early titration. There were no obvious effects on fetal growth parameters, fetal GH, or fetal IGF-I. In addition, the baby was healthy and showed no adverse signs. Very low pegvisomant levels were measured in cord blood, indicative of either minimal transplacental passage or, more likely, contamination by maternal blood at collection. The patient also experienced spontaneous labor, and postpartum was able to lactate, indicating that pegvisomant likely did not cross-react with receptors for oxytocin and prolactin.

Ideally, acromegaly should be appropriately treated surgically before attempts at conception, predominately due to the potential untoward effects on maternal health, particularly in regard to the risk of gestational diabetes and hypertensive disorders. The optimal approach to women with active acromegaly (e.g. before surgical intervention or whose disease persists despite transsphenoidal adenomectomy) who become pregnant is controversial. Dopamine agonists are frequently not effective, and although cabergoline is often more useful than bromocriptine, its safety during gestation is not well documented. There are also recent concerns about this drug’s effect on serotonergic receptors, which may result in cardiac valvular pathology, albeit at much higher doses typically used in the treatment of Parkinson’s disease. Octreotide, which has pervasive effects on multiple hormone systems, is more effective in general than cabergoline, but experience with this agent in pregnant women is also very limited. Pegvisomant is highly effective (>90%) in normalizing IGF-I levels in patients with acromegaly, although it augments GH levels. Efficacy, safety, transplacental passage, and potential fetal effects of pegvisomant have not been previously explored in pregnant women.

During normal gestation, maternal pituitary GH secretion decreases, whereas IGF-I levels remain normal, although the levels are statistically higher in pregnant vs. nonpregnant women, the greatest concentrations being achieved during the third trimester (5). This phenomenon is suspected to be the result of the production of GHV, which appears to assume the direct stimulation of hepatic IGF-I production. In response, pituitary GH secretion is markedly attenuated during gestation. However, little is known about this relationship in the setting of active acromegaly, although increased GH and IGF-I typically persist in untreated patients, suggesting ongoing hypersecretion from the responsible pituitary adenoma. A recent report suggested that GH hypersecretion in acromegalic women may actually wane during gestation, allowing for a discontinuation of any medical therapy while pregnant (6), but this report will require confirmation by others.

Complicating any discussion concerning a drug that might modulate fetal growth and development is the fact that the prenatal GH-IGF-I system is itself not fully understood. However, it is well documented that three hormones are important for optimal fetal as well as placental growth: insulin, IGF-I, and IGF-II. The latter two are polypeptides homologous in sequence to insulin that influence somatic cell growth and proliferation (7, 8). Both IGF-I and IGF-II knockout mice are 60% the size of controls, and the combination of IGF-I/IGF-II knockout mice demonstrates an additional 30% reduction in body weight (9). Some IGF-I and IGF-I receptor knockouts may also demonstrate a birth-lethal phenotype of organ hypoplasia and severely dystrophic muscles (10). Humans with a mutation in the IGF-I receptor gene demonstrate poor pre- and postnatal growth patterns. In contrast, IGF-II receptor deletions and a higher molar IGF-II to IGF-II receptor ratio are associated with fetal overgrowth and large size at birth (10, 11). This suggests that positive effects of IGF-I and IGF-II on fetal growth act through the IGF-I receptor, with growth inhibitory effects at the IGF-II receptor.

In theory, if pegvisomant crossed the placenta in a sufficient quantity, it could cause disruption of fetal growth by blocking GH receptors and interfere with fetal IGF levels. However, although the significance of the IGF system in fetal growth is reasonably well established, that of GH is not. Traditionally, it has been felt that GH actually plays little or no role in fetal growth because the fetus uses other methods of stimulating its own IGF-I production, such as placental lactogen (12). In support of this, GH deficiency due to deletions in the GH gene or GH receptor, pituitary aplasia/hypoplasia, or anencephaly, is associated with normal or near-normal size at birth (13, 14, 15), although human newborns may demonstrate certain anatomical and metabolic anomalies, such as micropenis, hypoglycemia, and conjugated hyperbilirubinemia (16). A GH receptor/GH-binding protein knockout mouse has severe growth retardation and diminished serum IGF-I levels, but only postnatally. These data suggest the supremacy of other factors that control growth and development in utero. (17). Although postnatal IGF-I production is dependent on hepatic GH receptors, GH receptor mRNA and receptor binding in the fetal liver are low (18). Instead, prenatal IGF-I levels may be controlled by other nutritional and metabolic factors. One study demonstrated increased cord blood levels of GH and IGF-I in the setting of pregnancy involving malnourished mothers, suggesting a potential fetal dynamic stress response, with unclear implications (8). However, there is some evidence that, at least in mice, GH may be important during early embryogenesis, implantation, and blastocyst development. In murine models, GH receptor transcripts can be detected in the preimplantation embryo as early as the two-cell stage (19). In summary, the data suggest that although pituitary GH may be important early in embryogenesis, the regulation of fetal growth and IGFs proceeds in a largely GH-independent manner. The data collected in our patient suggest that pegvisomant does not substantially cross the placenta, and has no effect on fetal GH and IGF-I interactions.

Pegvisomant could also, in theory, interfere with normal placental GHV dynamics when used in pregnant women. It remains controversial whether GHV, produced by the syncytiotrophoblast cell layer and the main maternal GH during gestation, is necessary to maintain a healthy pregnancy. One group of investigators demonstrated decreased circulating GHV in maternal blood and mRNA in the placenta in the setting of intrauterine growth retardation (20). However, little is known about GHV in acromegaly. Beckers et al. (21) reported two cases of acromegalic patients in which GHV was not suppressed during pregnancy, demonstrating that its secretion is not suppressed by pituitary GH hypersecretion. Our patient and baby both had normal placental GHV levels, despite the presence of circulating pegvisomant. There is a paucity of information in the literature concerning the control of placental GHV secretion. However, it is believed that GHV binds to the GH receptor similar to GH (22, 23). The GHV concentration remaining within the normal range suggests that it is constitutively secreted by the placenta without negative feedback from maternal GH or IGF-I.

The data collected from this unique case suggest that pegvisomant therapy during gestation may be both safe and effective in maintaining normal IGF-I in the mother. Moreover, transplacental passage of pegvisomant is either absent or minimal, with a concentration highly unlikely to convey any significant pharmacodynamic effects on the fetal GH and IGF-I system. Finally, there is no evidence of substantial secretion into breast milk, although, admittedly, even if ingested by the baby, gastric hydrolysis would likely rapidly inactivate this peptide. This limited data set provides some preliminary evidence that pegvisomant therapy, if needed for active acromegaly, may be continued cautiously during pregnancy without undue concerns regarding fetal growth and development. Clearly, however, further study is necessary before we fully understand the efficacy and safety of this new drug during pregnancy.


   Footnotes
 
Disclosure Information: S.R.B. has nothing to disclose. S.E.I. has served as an advisor to Pfizer. S.A.W. currently receives lecture fees from Pfizer and has previously served as an advisor for Pfizer. M.B. has previously received lecture fees from Pfizer. M.P.W. is an employee of Pfizer.

First Published Online June 26, 2007

Abbreviation: GHV, GH variant.

Received May 3, 2007.

Accepted June 20, 2007.


   References
Top
 Abstract
 Introduction
 Subject and Methods
 Results (Table 1)
 Discussion
 References
 

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