Review Article Hypopituitarism and Successful Pregnancy

Int J Clin Exp Med 2014;7(12):4660-4665 www.ijcem.com /ISSN:1940-5901/IJCEM0002633

Review Article Hypopituitarism and successful pregnancy

Xue Du*, Qing Yuan*, Yanni Yao, Zengyan Li, Huiying Zhang

Department of Obstetrics and Gynecology, General Hospital, Tianjin Medical University, Tianjin, China Received September 19, 2014; Accepted November 24, 2014; Epub December 15, 2014; Published December 30, 2014

Abstract: Hypopituitarism is a disorder characterized by the deficiency of one or more of the hormones secreted by the pituitary gland. Hypopituitarism patients may present the symptoms of amenorrhea, poor pregnancy potential, infertility, and no production of milk after delivery. Successful pregnancy in hypopituitarism patient is rare because hypopituitarism is associated with an increased risk of pregnancy complications, such as abortion, anemia, pregnancy-induced hypertension, placental abruption, premature birth, and postpartum hemorrhage. Hypopituitarism during pregnancy and perinatal period should be managed carefully. The hormone levels should be restored to normal before pregnancy. GH and HMG-hCG are combined to improve follicular growth and the success rate of pregnancy. Hypopituitary patients must be closely monitored as changes may need to be made to their medications, and serial ultrasound measurements are also necessary for fetal growth assessment.

Keywords: Hypopituitarism, assisted reproductive techniques, pregnancy, hormone replacement

Introduction pregnancy. Hypopituitarism is associated with an increased risk of pregnancy complications, Pituitary gland is the most important endocrine such as abortion, anemia, pregnancy-induced gland in the body, and composed of adenohy- hypertension, placental abruption, premature pophysis (anterior pituitary) that secretes birth, and postpartum hemorrhage [3-5]. The gonadotropins (FSH and LH), TSH, ACTH, GH, advance of assisted reproductive techniques and prolactin (PRL), and neurohypophysis (pos- makes it possible to improve the pregnancy terior pituitary) that stores antidiuretic hormone rate in hypopituitary patients. This highlights (ADH) and oxytocin released in the hypothala- the need for an accurate assessment and treat- mus. These hormones play important roles in a ment of this disease during pregnancy and peri- wide variety of physiological processes, includ- natal period. The common types of hypopituita- ing metabolism, growth and development, and rism include Simmonds’ syndrome, also refer- reproduction. Hypopituitarism is a disorder red to as Sheehan’s syndrome that occurs as a characterized by the deficiency of one or more result of ischemic pituitary necrosis due to of the hormones secreted by the pituitary severe postpartum hemorrhage, and pituitary gland. It has been suggested that damage to > dwarfism which is characterized by small stat- 50% of pituitary gland may inhibit the secretion ure but normal body proportions due to growth of anterior pituitary hormones, which in turn hormone deficiency in childhood. may affect a variety of target organs, including ovary, thyroid gland, and adrenal gland. The Dökmetaş et al. [6] investigated the clinical deficiencies of growth hormone (GH), follicle- characteristics of Sheehan’s syndrome in 20 stimulating hormone (FSH) and luteinizing hor- patients, and found that hypopituitarism due to mone (LH) are the most commonly encountered Sheehan’s syndrome could be of different [1], whereas the deficiencies of adrenocortico- degrees of severity, ranging from partial failure trophic hormone (ACTH) and/or thyroid-stimu- to panhypopituitarism. Panhypopituitarism has lating hormone (TSH) are the least [2]. been reported to occur in between 55% and Therefore, it is still possible for patients with 86% of patients with Sheehan’s syndrome, and partial necrosis of anterior pituitary to have a almost all of these patients have GH deficiency. normal ovulatory function, and even to achieve The most common causes of hypopituitarism Hypopituitarism and pregnancy are pituitary adenomas and postpartum hem- [4] found that only one patient could breastfeed orrhage, the clinical manifestations of which her baby. vary considerably, depending on the severity of hormone deficiency and the atrophy of target gla- Maternal thyroid deficiency may be detrimental nds. Patients may have isolated or combined to fetal brain development [9], and the infants pituitary hormone deficiencies, and impairment could develop respiratory distress syndrome of hormone secretion usually occurs in the and have a high risk of cognitive disorders. order of gonadotropin, thyroid hormone, and Lazarus et al. [10] showed that perinatal thyroid adrenocorticotropic hormone. Patients with dysfunction caused a significant reduction in hypogonadism may present symptoms of atro- body weight and height, delayed neurodevelop- phic breast, amenorrhea, infertility, and no pro- ment, and depression-like behaviors of the duction of milk after delivery. In recent years, infants. This is because that approximately one the rapid development of endocrinology and third of maternal thyroid hormone is delivered imaging techniques contributes significantly to to the fetus, and it plays an important role in the detection and treatment of pituitary tumors. fetal neurodevelopment in the first half of preg- However, due to the increasing incidence of nancy prior to fetal pituitary-thyroid axis devel- hypopituitarism in young adults who wants chil- opment [1]. Alexander et al. [11] showed an dren, the preparation and perinatal treatment association between gestational hypopituita- of hypopituitarism have become a topic of rism and impaired intellectual and cognitive interest. development in offspring, and Wada et al. [12] also showed irreversible damage to the audito- Effects of hypopituitarism during pregesta- ry system functions caused by perinatal hypo- tional, gestational, and postnatal period thyroidism in rats.

Hypopituitary patients may present the symp- Treatment of hypopituitarism toms of amenorrhea, poor pregnancy potential, and infertility. In addition, hypopituitarism has General treatment been reported to be associated with an increased risk of pregnancy complications, including Replacement of deficient hormones remains high rate of abortion during early gestation and the main treatment modality for hypopituita- postpartum uterine inertia, thus leading to rism, and the order of treatment is glucocorti- postpartum hemorrhage and poor pregnancy coid, thyroid hormone, sex hormone, and outcomes. Idris et al. [7] retrospectively studied growth hormone. In general, thyroid hormone 167 pregnancies managed in the antenatal replacement should be initiated two weeks endocrine clinic, and showed that the cesarean after glucocorticoid replacement, and it is section rate was significantly higher in hypopi- advisable to begin with low dosage to prevent tuitary patients (28.7%) than in normal local addisonian crisis. women (18%). Preparation before pregnancy Breastfeeding in the postpartum period depe- nds to a great extent on the PRL level of the Adult hypopituitary patients with hypogonad- mother. Although failure of milk production is a ism should also receive hormones to maintain typical symptom of Sheehan’s syndrome, hyper- the secondary sex characteristics and uterine prolactinemia has also been reported in pati- reproductive function. Artificial cycle treatment ents with Sheehan’s syndrome [1]. PRL defi- could stimulate the proliferation of endometri- ciency is common in panhypopituitary patients um and vaginal epithelium. It also allows the [8]. Hyposecretion of PRL can lead to failure of vaginal superficial cells to be epithelialized, and milk production in the postpartum period; on leads to increase in intracellular glycogen. The the other hand, hypersecretion of PRL can lead breakdown of glycogen to lactic acid is expect- to galactorrhea and nipple tenderness, neither ed to be beneficial for vaginal self-cleaning and of which is suitable for breastfeeding. Thus, maintenance of secondary sex characteristics. hypopituitary patients generally do not have Thus, sequential replacement of estrogen and sufficient milk production to breastfeed their progesterone is a viable method to promote babies. In a retrospective study of 18 pregnan- uterine development and prepare for pregnancies in 9 hypopituitary patients, Overton et al. cy. The hormone levels should be restored to

4661 Int J Clin Exp Med 2014;7(12):4660-4665 Hypopituitarism and pregnancy normal before pregnancy. High-dose estrogen The mechanisms of GH responsible for the and GH could improve the prognosis of hypopi- improved pregnancy outcomes may be that: (1) tuitarism, and GH is helpful for the preparation GH can stimulate follicular growth and matura- of uterus and conception [1]. However, in hypo- tion, and it may also facilitate ovulation by pituitary patients with hyperprolactinemia, it is increasing the sensitivity of ovarian response desirable to reduce the prolactin level to nor- to gonadotropins, such as LH and FSH, and by mal prior to the artificial cycle treatment to reducing the rate of apoptosis in preovulatory induce ovulation. Patients can be treated with ovarian follicles, which is thought to be IGF-I human menopausal gonadotropin (HMG) and mediated, while GH has no such effect in preg- human chorionic gonadotropin (hCG) during nant women with normal pituitary function [17]; preparation for pregnancy. Thomas et al. [8] (2) GH/IGF-1 has a role in fertility disorders showed that the combination of GH and HMG- caused by pituitary hormone and gonadotropin hCG promoted follicular growth and improved deficiencies. GH/IGF-1 signaling transmission the success rate of pregnancy. is important in patients with infertility or diffi- culty in conception caused by GH deficiency; Assisted reproductive technique and (3) GH/IGF-1 can improve egg fertilization, and thus helps to improve infertility due to fer- Gonadotropin treatment can successfully in- tilization problems [1, 13, 17]. Thus, GH should duce follicle formation in most hypopituitary be used to normalize the IGF-1 and/or GH level patients, but higher doses of gonadotropins are to improve the success of pregnancy prior to required for stimulation of follicular growth in ovulation induction. these patients as compared with other causes of anovulation [13]. Some patients respond Treatment during pregnancy poorly to HMG-hCG protocol, probably due to the diminished ovarian reserve in these The symptoms can be improved or even elimi- patients [14]. Pulsatile gonadotropin releasing nated in some hypopituitary patients after hormone (GnRH) appears to be ineffective in pregnancy due to the partial or complete com- the treatment of pituitary gland diseases [4], pensation of the function of pituitary gland, and thus patients with hypopituitarism and gonado- thus it does not necessarily need hormone tropin deficiency can be treated with hormones replacement therapy. This can be attributed to with LH activities to allow for an adequate the fact that the physiological changes during response to estrogen. Thomas et al. [8] also pregnancy stimulate the proliferation of residu- proposed to use HMG and recombinant FSH al pituitary gland and abundant blood supply, (including FSH and LH) to induce ovulation. If leading to the improvement of pituitary function the hypopituitary patients respond poorly to and eventually disappearance of clinical symp- traditional ovulation induction treatment, GH toms. It has been suggested that placenta replacement can be applied prior to the ovula- could compensate for the endocrine function of tion induction [5]. A panhypopituitary female pituitary gland, thus the symptoms may reap- with poor response to gonadotropin took GH pear after delivery. Hypopituitary patient with replacement for 4 months until the serum level LH deficiency could receive luteal support with of insulin-like growth factor-I (IGF-I) was normal- micronised progesterone administered intrave- ized, then she began ovulation induction with nously, orally, or vaginally until the 12th week of gonadotropins and transdermal estradiol and gestation to avoid early pregnancy loss (placen- become pregnant [14]. Another 31-year-old nul- ta can produce sufficient amount of progester- liparous woman with hypopituitarism and GH one to maintain early pregnancy) [8]. deficiency took GH replacement for 5 months prior to ovulation induction with HMG, ultimate- A patient with Sheehan’s syndrome and anteri- ly resulting in normalization of IGF-I levels and or pituitary insufficiency became pregnant successful pregnancy [15]. It has also been spontaneously, and her thyrotropic function reported that a woman with adult growth hor- recovered after delivery [18]. A large amount of mone deficiency (AGHD) became pregnant after thyroid hormone and adrenaline are needed to GH treatment [8]. Kitajima et al. [16] reported maintain maternal and fetal endocrine func- that the application of HMG-hCG successfully tion, thus hypopituitary patients should be induced ovulation and pregnancy in a patient closely monitored for hormone levels during with normal serum GH and IGF-1. pregnancy, and it is crucial to adjust the dose of

4662 Int J Clin Exp Med 2014;7(12):4660-4665 Hypopituitarism and pregnancy hormone replacement accordingly. Kitajima et Considerable evidence has accumulated that al. [16] reported that a hypopituitary woman pregnancies in women with hypopituitarism are with hyperprolactinemia was treated with mes- at increased risk of pregnancy complications, tranol and dihydroprogesterone for luteal sup- thus it is crucial to monitor maternal and fetal port until the 8th week of gestation. Thus, close hormone levels, and serial ultrasound mea- monitoring during pregnancy appears to be surements are also necessary for fetal growth mandatory in hypothyroid women. assessment. Although twin pregnancy carries a particularly poor outcome and thus should be A great amount of thyroid hormone is needed to avoided at all costs [4], Kitajima et al. [16] meet maternal and fetal need during pregnan- reported successful twin pregnancy in a woman cy, thus serum TSH and free thyroxine (FT4) with hypopituitarism caused by a suprasellar measurements are mandatory in pregnant germinoma, and then pointed out that hormone patients, and an increase in daily doses of L-T4 replacement after ovulation induction was nec- is necessary to maintain FT4 at a high level (> essary for these patients to achieve pregn- 19.3 pmol/L; normal range, 10.3-25.8 pmol/L) ancy. [8, 19]. Wang et al. [20] retrospectively studied the perinatal care, treatment, and pregnancy Uterine size is reported to be similar in hypopi- outcomes in 31 hypopituitary women, and the tuitary patients [1], thus uterine size alone results showed that there was no significant could not explain the poor pregnancy outcomes difference in LT4 dosage between early preg- of hypopituitarism. For this reason, the poor nancy (51 ± 36 μg/d) or postpartum (38 ± 34 pregnancy outcomes are more likely to be relat- μg/d) and pre-gestation (33 ± 35 μg/d) (P > ed to pituitary hormone deficiencies.Overton et

0.05). However, the required dose of LT4 at the al. [4] showed that patients with only GH defi- second (68 ± 42 μg/d) and third trimester (76 ± ciency had more favorable outcome than those 42 μg/d) was increased by about 35% on aver- with panhypopituitarism. However, GH deficien- age as compared to the pre-gestational period cy is unlikely to be the main contributor to the

(P < 0.05). It has also been shown that LT4 poor pregnancy outcomes because placental requirements increased during early pregnancy GH can compensate for its action during gesta- in most women with primary hypothyroidism, tion. GH replacement is effective during early reaching a plateau after 16 to 20 weeks of ges- pregnancy [13, 20]. Muller et al. [24] showed tation at a value about 47% higher than the pre- that GH treatment reduced the abortion rate in pregnancy value and persisting throughout patients with GH deficiency [13]. Daviset al. [5] pregnancy [21]. showed that maternal implications were more impressive in 14 overtly hypothyroid patients Glucocorticoid therapy in pregnancy should than in 12 subclinical hypothyroid patients, and take into account that adrenal reserve increas- that overt thyroid deficiency was associated es as pregnancy progresses, and salivary free with adverse pregnancy outcomes, which could cortisol (SaFC) is a more consistent, corticoste- be improved by thyroxine replacement. Kübler roid-binding globulin independent, and physio- et al. [3] analyzed 31 pregnancies in 27 hypopi- logically rational measure of adrenal function in tuitary women, and found that oxytocin supple- pregnancy rather than serum total cortisol [22]. mentation helped establish the physiologic Patients on glucocorticoid replacement may conditions and prevent postpartum uterine need to increase their hydrocortisone dose by inertia. It may have contributed to correct fetal 50% during the last trimester of pregnancy, and presentation, but could not prevent postpar- by the start of the labor, the hydrocortisone tum hemorrhage in patients with severe hypopi- dose should be increased to stress doses until tuitarism. Hypopituitarism may not be an abso- 48 h postpartum [1]. Wiren et al. [23] followed lute indication for cesarean delivery, but it is 8 hypopituitary women during their 12 distinct associated with an increased risk of pregnancy pregnancies, and found that GH replacement complications, thus a more liberal indication for was maintained at the same pregestational cesarean delivery is preferred in these patients. dose during the first trimester, with a gradual decrease of the dose during the second trimes- Treatment of infants ter and discontinuing the treatment at the beginning of the third trimester, and all of the Maternal hormone deficiencies and replace- 12 pregnancies were successful. ment may have adverse effects on their infants,

4663 Int J Clin Exp Med 2014;7(12):4660-4665 Hypopituitarism and pregnancy and close follow up is thus mandatory. However, [4] Overton CE, Davis CJ, West C, Davies MC, Con- a number of studies have shown that GH treat- way GS. High risk pregnancies in hypopituitary ment during early pregnancy had no long-term women. Hum Reprod 2002; 17: 1464-1467. adverse effect on mothers and their babies, [5] Davis LE, Leveno KJ, Cunningham FG. Hypothy- roidism complicating pregnancy. Obstet Gyne- and patients who received GH therapy for 6-12 col 1988; 72: 108-112. months until pregnancy had uneventful preg- [6] Dökmetaş HS, Kilicli F, Korkmaz S, Yonem O. nancies, full-term deliveries, and healthy ba- Characteristic features of 20 patients with bies with normal stature in length and weight Sheehan’s syndrome. Gynecol Endocrinol [13]. However, as the glucocorticoid can pass 2006; 22: 279-283. to breast milk, whether it has a detrimental [7] Idris I, Srinivasan R, Simm A, Page RC. Mater- effect on the infants needs to be further stud- nal hypothyroidism in early and late gestation: ied. It is believed that the amount of glucocorti- effects on neonatal and obstetric outcome. coid in breast milk is insufficient to affect neo- Clin Endocrinol (Oxf) 2005; 63: 560-565. [8] Thomas VP, Sathya B, George S, Thomas N. natal adrenal functions. Pregnancy in a patient with hypopituitarism fol- Conclusions lowing surgery and radiation for a pituitary ad- enoma. J Postgrad Med 2005; 51: 223-224. [9] Casey BM, Dashe JS, Wells CE, McIntire DD, Hypopituitarism during pregnancy and perina- Byrd W, Leveno KJ, Cunningham FG. Subclini- tal period should be managed carefully. The cal hypothyroidism and pregnancy outcomes. hormone levels should be restored to normal Obstet Gynecol 2005; 105: 239-245. before pregnancy. GH and HMG-hCG are com- [10] Lazarus JH. Thyroid disease in pregnancy and bined to improve follicular growth and the suc- childhood. Minerva Endocrinol 2005; 30: 71- cess rate of pregnancy. Hypopituitary patients 87. must be closely monitored as changes may [11] Alexander EK, Marqusee E, Lawrence J, Jaro- need to be made to their medications, and seri- lim P, Fischer GA, Larsen PR. Timing and mag- nitude of increases in levothyroxine require- al ultrasound measurements are also neces- ments during pregnancy in women with sary for fetal growth assessment. hypothyroidism. N Engl J Med 2004; 351: 241- 249. Acknowledgements [12] Wada H, Yumoto S, Iso H. Irreversible damage to auditory system functions caused by perina- This study was supported by the National tal hypothyroidism in rats. Neurotoxicol Teratol Natural Science Foundation of China (grant No. 2013; 37: 18-22. 81303108). [13] Sakai S, Wakasugi T, Yagi K, Ohnishi A, Ito N, Takeda Y, Yamagishi M. Successful pregnancy Disclosure of conflict of interest and delivery in a patient with adult GH deficiency: role of GH replacement therapy. Endocr None. J 2011; 58: 65-68. [14] Park JK, Murphy AA, Bordeaux BL, Dominguez Address correspondence to: Zengyan Li, Department CE, Session DR. Ovulation induction in a poor of Obstetrics and Gynecology, General Hospital, responder with panhypopituitarism: a case re- Tianjin Medical University, Tianjin, China. E-mail: port and review of the literature. Gynecol Endo- [email protected] crinol 2007; 23: 82-86. [15] Daniel A, Ezzat S, Greenblatt E. Adjuvant References growth hormone for ovulation induction with gonadotropins in the treatment of a woman [1] Karaca Z, Tanriverdi F, Unluhizarci K, Kele- with hypopituitarism. Case Rep Endocrinol stimur F. Pregnancy and pituitary disorders. 2012; 2012: 356429. Eur J Endocrinol 2010; 162: 453-475. [16] Kitajima Y, Endo T, Yamazaki K, Hayashi T, [2] Dong AM, Yin HF, Gao YM, Guo XH. Spontane- Kudo R. Successful twin pregnancy in panhy- ous pregnancy in a patient with lymphocytic popituitarism caused by suprasellar germino- hypophysitis. Beijing Da Xue Xue Bao 2009; ma. Obstet Gynecol 2003; 102: 1205-1207. 41: 242-244. [17] Giampietro A, Milardi D, Bianchi A, Fusco A, [3] Kübler K, Klingmüller D, Gembruch U, Merz Cimino V, Valle D, Marana R, Pontecorvi A, De WM. High-risk pregnancy management in Marinis L. The effect of treatment with growth women with hypopituitarism. J Perinatol 2009; hormone on fertility outcome in eugonadal 29: 89-95. women with growth hormone deficiency: report

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