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Pregnancy in Acromegaly: Successful Therapeutic Outcome¹

Division of Endocrinology and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Dr. Shlomo Melmed, Cedars-Sinai Medical Center, Division of Endocrinology and Metabolism, 8700 Beverly Boulevard, Becker B-131, Los Angeles, California 90048. E-mail: melmed{at}CSMC.edu

	Introduction

Top Introduction Case 1 Obstetric history Case 2 Case 3 Case 4 Discussion References

 
Acromegaly usually results from GH hypersecretion elaborated by a somatotroph adenoma. With the advent of advanced surgical and medical management of these patients, increasing numbers of women with the disorder are choosing to become pregnant. Several factors may impact the course of pregnancy in acromegaly. As the pituitary controls the gonadotropin axis, perturbed pituitary function often leads to infertility or early pregnancy termination due to failure to maintain intrauterine implantation. Furthermore, GH is a potent insulin antagonist, and pregnant patients with GH hypersecretion are therefore prone to added glucose intolerance (1).

In contrast, pregnancy itself may impact on the course of the pituitary tumor. During pregnancy, the normal pituitary increases in size (2), and therefore, tumors are at risk for hemorrhage due to enhanced pituitary vascularity and edema in addition to estrogen-mediated pituitary hyperplasia (3). We here report the course of successful pregnancy in four patients with acromegaly.

	Case 1

Top Introduction Case 1 Obstetric history Case 2 Case 3 Case 4 Discussion References

 
A 30-yr-old Caucasian female presented with a 12-yr history of gradual change in appearance, headache, increase in shoe and ring size, acne, hirsutism, and skin tags. She also experienced carpal tunnel syndrome, overbite, and widening of incisor spaces. Nine months before diagnosis, she developed galactorrhea and amenorrhea. After parlodel administration, she underwent transsphenoidal removal of a GH-secreting pituitary adenoma, with an excellent symptomatic response. Postoperative magnetic resonance imaging (MRI) revealed minimal residual enhancing tissue in the sella turcica and a partially empty sella. Random GH and insulin-like growth factor I (IGF-I) levels were 10 (normal, <10 ng/mL) and 591 (normal, 123–463 ng/mL) respectively.

	Obstetric history

Top Introduction Case 1 Obstetric history Case 2 Case 3 Case 4 Discussion References

 
In 1987, 6 yr before diagnosis, the patient discontinued oral contraceptive pills, but was unable to become pregnant. After transsphenoidal surgery, her periods became regular, and 6 months later, she conceived. No symptom exacerbation occurred during pregnancy, and IGF-I and PRL levels were both in the normal ranges for pregnancy. Oral glucose tolerance tests performed during pregnancy at 3, 6, and 9 months yielded respective 2-h GH levels of 0.1, 0.8, and 1.5 ng/mL.

A normal full-term infant was delivered. Five months postpartum, the GH level measured 2 h after oral glucose administration was 1.1 ng/mL, and the pituitary MRI scan showed no change. One year postpartum, however, the postglucose GH level was 3.9 ng/mL despite an IGF-I level of 364 ng/mL (normal, 114–483 ng/mL). An octreoscan also revealed enhanced pituitary uptake; consequently, therapy with octreotide was initiated.

	Case 2

Top Introduction Case 1 Obstetric history Case 2 Case 3 Case 4 Discussion References

 
A 31-yr-old Caucasian female was assessed for nausea, headache, and vomiting. Two years previously, she had undergone transsphenoidal resection of a GH-secreting pituitary macroadenoma with supraseller and cavernous sinus extension. She had experienced secondary amenorrhea for 8 yr before surgery. Postoperative MRI revealed residual tumor in the sphenoid sinus, and a random GH measurment was 17 ng/mL. Six months postoperatively, postglucose GH was 34 ng/mL, with an elevated IGF-I level (308 ng/mL). Octreotide treatment was initiated (50 µg, sc, three times daily) and suppressed GH to 1.8 ng/mL 2 h after a morning injection. However, the patient discontinued octreotide after 1 month due to nausea, vomiting, and diarrhea. Six months later, she became pregnant and vaginally delivered a normal full-term infant.

The patient had also delivered three normal full-term infants by cesarean section during the time when she had symptomatic evidence of acromegaly (assessed in retrospect). She had, in fact, received ovulation induction treatment for her second pregnancy because of the amenorrhea. After pituitary surgery, her menstrual cycles returned to normal.

	Case 3

Top Introduction Case 1 Obstetric history Case 2 Case 3 Case 4 Discussion References

 
A 28-yr-old Caucasian female was diagnosed with acromegaly when she presented with failure to lactate postpartum. Twenty-five percent of her macroadenoma mass was removed by transsphenoidal resection, and she received subsequent postoperative pituitary radiation. She was treated with parlodel for 2 yr until octreotide was started, which suppressed IGF-I levels from 5.4 to 1.8 U/mL and GH to 1.6 ng/mL 2 h after injection. Soft tissue swelling and acne improved, energy level increased, and menses returned to normal. She continued octreotide (100 µg, sc, three times daily) for 3 yr until becoming pregnant for the second time. Octreotide was then discontinued, and visual field examinations and postglucose GH levels were assessed every 4–6 weeks. At 3 months, the postglucose GH level was 11.5 ng/mL, and IGF-I was 356 (normal, 114–492); at 6 months, GH was 2.9 ng/mL, and IGF-I was 427; and at 7 months, GH was 22 ng/mL, and IGF-I was 564 ng/mL. She delivered a normal, full-term infant.

	Case 4

Top Introduction Case 1 Obstetric history Case 2 Case 3 Case 4 Discussion References

 
A 30-yr-old Caucasian female presented with a 1-yr history of amenorrhea. Examination revealed clinical features suggestive of acromegaly, including large hands, broad feet, and prominent nose. The IGF-I level was 1719 ng/mL (upper normal limit, 492 ng/mL), a random GH measurment was 260 ng/mL, and PRL was normal. MRI revealed a pituitary macroadenoma with suprasellar extension and extension into the right cavernous sinus. The patient had transsphenoidal removal of the pituitary adenoma 1 month after diagnosis.

Postoperatively, amenorrhea persisted with increases in shoe and ring size. Three months postoperatively, the IGF-I level was 1016 ng/mL, and an oral glucose tolerance test revealed a basal GH level of 37 ng/mL, which suppressed to 14 ng/mL 2 h after oral glucose. She was started on octreotide and despite increasing doses demonstrated persistently elevated IGF-I and nonsuppressible GH levels. While receiving 1200 µg octreotide/day, the IGF-I level was 1106 ng/mL, and GH assayed 2 h after injection was 8.6 ng/mL. Postoperative MRI revealed persistent tumor in the sella with some normal gland as well as residual tumor in the cavernous sinus. Because of persistent GH hypersecretion, despite maximal doses of octreotide, the patient underwent repeat transphenoidal surgery 2 yr after initial surgery. Tumor encased in the scar as well as in the cavernous sinus could not be removed, and the patient was treated with -knife irradiation 1 yr after the second transsphenoidal surgery. Six months later, GH concentrations 2 h after oral glucose were 4.2 ng/mL, and the IGF-I level was 663 ng/mL. Octreotide treatment was reinitiated (100 µg three times daily). GH levels fell to 2.2 ng/mL 2 h after octreotide injection, and the IGF-I level was 662 ng/mL. Two months after -knife irradiation, the patient began menstruating regularly.

Six months after GH and IGF-I normalization, the patient became pregnant, and octreotide was discontinued. Currently, she is 7 months pregnant and is being evaluated for signs of tumor enlargement monthly and for visual field assessment every 4–6 weeks.

	Discussion

Top Introduction Case 1 Obstetric history Case 2 Case 3 Case 4 Discussion References

 
We report here a spectrum of four different cases of pregnancy occurring in patients harboring GH-secreting pituitary tumors. The first patient became pregnant 7 months after successful surgical removal of a GH-secreting macroadenoma. Four months after delivery of a normal full-term infant, she developed recurrent GH hypersecretion.

The second patient has been pregnant seven times while experiencing active clinical and biochemical acromegaly. She had five pregnancies, resulting in three normal full-term births and two miscarriages before the diagnosis of acromegaly, and required fertility treatment for the fourth pregnancy. Incomplete resection of a GH-secreting macroadenoma resulted in persistent postoperative biochemical GH hypersecretion. The patient was noncompliant with octreotide treatment and became pregnant 14 months postoperatively even though her GH levels were elevated. The fetus died in utero at 5 months gestation, associated with the development of anticardiolipin antibodies in the patient. One month after dilation and curettage, the patient again became pregnant.

The third patient was diagnosed with acromegaly after her first delivery. Incomplete transsphenoidal resection of a GH-secreting macroadenoma followed by pituitary radiation necessitated octreotide treatment, with an excellent biochemical response. After 3 yr, the patient again became pregnant. At this time, octreotide was discontinued, and she delivered a normal full-time infant.

The fourth patient had an initial incomplete transsphenoidal resection of a GH-secreting pituitary tumor, followed by a second pituitary resection and -knife irradiation. Persistently elevated GH levels postoperatively were normalized with octreotide treatment. The patient became pregnant, octreotide was discontinued, and the patient is currently being followed for signs of tumor enlargement during the pregnancy.

Acromegaly and fertility

Reports of pregnancy occurring in acromegalic patients are uncommon. Menstrual irregularities are an early and frequent finding in acromegaly (4). Several mechanisms may contribute to amenorrhea and infertility in acromegaly. Hypopituitarism and decreased gonadotropin reserve may be caused by the expanding tumor mass. Hyperprolactinemia occurs in 30–40% of acromegalic patients (5) and results in hypothalamic-pituitary-ovarian axis dysfunction at several levels, including reduction in pulsatile GnRH secretion (6, 7) as well as hypoestrogenism (8). Normalization of hyper-prolactinemia frequently restores menstruation and fertility. GH and IGF-I also regulate ovarian function. GH increases ovarian responsiveness to gonadotropins (9), thereby sensitizing the ovary to the stimulatory effects of gonadotropins. GH also stimulates local IGF-I production in the ovarian follicle (10). Whether GH acts directly on the ovary or whether its sensitizing effect is mediated by IGF-I is as yet unclear.

A review of the current literature revealed 24 cases of pregnancy and acromegaly subsequent to the 34 cases initially reported in the 1950s (11). Reported pregnancies occurred in the context of a wide spectrum of clinical scenarios of acromegaly, ranging from undiagnosed, untreated acromegaly (11, 12, 13) to patients treated with bromocriptine (14, 15, 16), octreotide (17, 18), and transsphenoidal surgery without (19, 20) or with (21) fertility treatment. The majority of reported cases were treated with bromocriptine only (14, 15, 16) or in conjunction with radiation (22, 23) or surgery (24). Bromocriptine was not associated with teratogenicity or fetoplacental insufficiency in three cases (14, 15, 16); however, prematurity was reported in one patient (16), and intra-uterine growth delay (13, 23) has been reported in two cases. There are four cases (including our two cases) of pregnancy ensuing after successful treatment of acromegaly with octreotide (17, 18). In all cases, octreotide was discontinued when pregnancy was diagnosed. Intrauterine fetal exposure to octreotide for the first month did not cause notable fetal malformations. Pregnancy has occurred after surgical intervention alone (19, 25) despite the persistence of GH hypersecretion (25). Selective transsphenoidal removal of GH-secreting microadenomas (19) with return of regular menses in half of the patients (12 of 23) resulted in three pregnancies.

GH physiology during normal pregnancy and acromegaly

Maternal circulating GH levels are derived from different sources depending on the trimester. In normal women during the first trimester (26, 27), GH is pituitary in origin and is secreted in a pulsatile pattern. Thereafter, placental GH, contributes the major component of circulating GH (26). This variant form of GH is secreted continuously rather than in a pulsatile pattern and is not detected by routine clinical RIA or immunoradiometric assay. RIAs using antibodies that recognize specific epitopes on the placental GH variant (26) distinguish pituitary from placental GH. These assays use two monoclonal antibodies, one of which recognizes pituitary and placental GH, the other of which recognizes only pituitary GH (Fig. 1). Thus, to diagnose acromegaly during pregnancy, specific RIAs for the placental variant are required to differentiate elevated GH levels from pituitary vs. placental sources.

View larger version (13K): [in this window] [in a new window]   Figure 1. GH profile throughout pregnancy (mean ± SEM). Graph A represents circulating levels of pituitary GH only, whereas B represents circulating levels of placental as well as pituitary GH variants. As pituitary GH secretion is suppressed during pregnancy, graph B values truly reflect placental GH secretion during the last trimester of pregnancy. (From Caufriez A, Frankenne F, Hennen G, Copinschi G. 1993 Regulation of maternal IGF-I by placental GH in normal and abnormal human pregnancies. Am J Physiol. 265:E572–E577, with permission.)

View larger version (27K): [in this window] [in a new window]   Figure 2. Proposed model for regulation of pituitary and placental GH secretion in normal and acromegalic women. (Adapted with permission from Melmed S. 1990 Acromegaly. N Engl J Med. 322:966–977; and Beckers A, Stevenaert A, Foidart J, Hennen G, Frankenne F. 1990 Placental and pituitary growth hormone secretion during pregnancy in acromegalic women. J Clin Endocrinol Metab. 71:725–731.)

The pituitary gland enlarges during normal pregnancy, and pituitary volume may increase by 45% during the first trimester (30). Pituitary enlargement is due to hyperplasia of mature lactotrophs with concomitant reduction in gonadotroph numbers (31). Large amounts of PRL are produced primarily by the increased lactotroph mass as well as by suppressed (as evidenced by low GH messenger ribonucleic acid content) pluripotent somatrotrophs that can engage in PRL production and can also transform to lactotrophs under specific conditions (32).

Theoretically, the stimulatory effect of peripheral hormone surges during pregnancy could cause adenoma enlargement due to tumor growth or hemorrhage, or tumor infarction in patients with GH adenomas. The normal increase in pituitary gland size during pregnancy also contributes to the mass pressure effect on the optic nerve. However, earlier reports did not confirm that macroadenomas posed a greater risk for visual loss during pregnancy than microadenomas (33, 34). A recent study showed that the risk of visual loss is small in pregnant patients harboring functioning and nonfunctioning pituitary microadenomas (35). However, patients with adenomas greater than 1.2 cm are at greater risk of developing visual loss during pregnancy. Imaging techniques employed in this latter study were more sensitive and precise than those used in previous studies.

In reviewing all cases reported in the literature, pregnancy exacerbated acromegaly in 4 of 24 (17%) patients, necessitating therapeutic abortion in one patient at 10 weeks because of active disease. Recurrence of GH hypersecretion and return of clinical signs of acromegaly (including headache, increase in glove and shoe size, and coarsening of facial features) was reported (23) in a patient in whom bromocriptine treatment was discontinued at the start of pregnancy. Another reported patient (18) developed signs of increased intracranial pressure at 39 weeks gestation. Cesarean section was performed for fetal distress, and the patient underwent transsphenoidal resection for reexpansion of the adenoma.

How does acromegaly influence pregnancy?

Metabolic and cardiovascular complications of acromegaly can potentially cause medical complications to the mother and fetus during pregnancy. GH antagonizes insulin action, resulting in carbohydrate intolerance in 60% and diabetes mellitus in 13–32% of patients (36). As pregnancy itself is an insulin-resistant state, the pregnant acromegalic patient is at greater risk for hyperglycemia. There is also an increased incidence of hypertension and coronary artery disease in acromegalic patients, which poses potential risks to the fetus. However, none of these potential complications of elevated GH have been shown to have a deleterious effect in pregnant acromegalic patients.

Consequences of treatment on pregnancy

Bromocriptine. This dopamine agonist has not been associated with increased complication risk during pregnancy or with congenital malformations when given through the first few weeks of gestation in hyperprolactinemic patients (5, 37). Nine years of follow-up of children born to mothers treated with bromocriptine in the first few weeks of pregnancy revealed no differences in teratogenicity compared to expected rates (38). Several amenorrheic acromegalic patients conceived after normalization of hyperprolactinemia with bromocriptine (14, 15, 16, 22). Uncomplicated delivery of normal infants occurs even when bromocriptine treatment is continued throughout the pregnancy (14, 16).

Octreotide. There are only two previously reported cases of pregnant acromegalic patients treated with octreotide during early pregnancy (17, 18). The pregnancies and deliveries were uneventful, and the infants were normal. However, octreotide should be discontinued during pregnancy until more safety data are obtained.

Surgery. There are no data pertaining specifically to the impact of transsphenoidal surgery during pregnancy. Although there is no reported increased incidence of congenital abnormalities, surgery during early pregnancy may be associated with an increased incidence of spontaneous abortion, probably due to anesthesia effects (39). However, other investigators report no significant difference in abortion and perinatal mortality rates but found a significant difference in prematurity (8% vs. 37%) in pregnant patients treated surgically for pituitary tumors (33).

Management of acromegaly in women of childbearing age

The aims of therapy in female acromegalic patients wishing to conceive are normalization of PRL and GH levels to promote fertility and conception, prevention of tumor expansion during pregnancy, and delivery of a normal full-term infant. Surgery and medical therapy have distinct advantages and disadvantages in the pregnant acromegalic patient.

Patients with microadenomas who are biochemically responsive and tolerant to medical management (bromocriptine or octreotide) can continue medical management and should be advised to discontinue treatment when pregnancy is confirmed. This approach has been shown to be safe for the fetus, and the risk of tumor enlargement for the mother is small. Alternatively, transsphenoidal resection of microadenomas before conception does not impair fertility. Pregnant patients with microadenomas should be assessed clinically during each trimester for symptoms of tumor enlargement (Fig. 3).

View larger version (23K): [in this window] [in a new window]   Figure 3. Algorithm for the management of pregnant acromegalic patients.

Pituitary MRI should be repeated postpartum in patients with micro- and macroadenomas to assess tumor size. If the tumor has, in fact, enlarged, patients should be followed by repeat imaging at 6-month intervals.

Women with microadenomas can breastfeed their infants, as there are no data to suggest that PRL elevation caused by breastfeeding causes tumor expansion.

	Footnotes

 
¹ This work was supported by the Steinberg Foundation and Grant DK-50238.

Received August 6, 1997.

Revised November 6, 1997.

Accepted November 13, 1997.

	References

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