Endocrine Journal 2011, 58 (1), 65-68

NOTE

Successful pregnancy and delivery in a patient with adult GH deficiency: role of GH replacement therapy
Satoko Sakai1), Takanobu Wakasugi1), Kunimasa Yagi2), Akitsu Ohnishi2), Naoko Ito2), Yoshiyu Takeda2) and Masakazu Yamagishi2)
1) 2)

Department of Endocrinology and Metabolism, Fukui Prefectural Hospital, Fukui 910-8526, Japan Graduate School of Medical Science, Department of Internal Medicine, Kanazawa University, Kanazawa 920-8641, Japan

Abstract. Adult growth hormone deficiency (AGHD) is a recently recognized endocrine disorder characterized by low peak GH levels during provocative tests. The AGHD has a negative impact on bone mineral density, skeletal muscle strength, physical capacity and psychosocial well-being. Furthermore, the girls with GHD have delayed pubertal development, and in adulthood present a condition of subfertility. Treatment for AGHD with GH replacement therapy has been officially approved since 2006 in Japan. The patient was diagnosed as pituitary dwarfism at age 9. She was treated with GH replacement therapy since diagnosis until her height reached 155cm at age 15. When she was 24 years old, she suffered from clinical symptoms relating to GH deficiency, and she visited our hospital for reintroduction of the therapy to alleviate these clinical symptoms. She has been treated with the replacement therapy since then. The patients dysmenorrhea improved. And she was found to be 8 weeks pregnant at age 28 years 7 months. We immediately ceased replacement therapy and carefully observed the patient, because it is not indicated for female patient with pregnancy. She delivered a healthy girl at 40 weeks of pregnancy, no recognizable side-effects were observed in either mother or baby. To our knowledge, there are no other reports of a Japanese patient becoming pregnant during GH replacement therapy, and few cases have been reported in other countries. It remains uncertain whether the therapy is safe and essential for fetal development, fertility, and continuation of pregnancy in AGHD subjects. Key words: Adult growth hormone deficiency, Pregnancy, GH replacement therapy, Healthy baby

ADULT growth hormone deficiency (AGHD) is a recently recognized endocrine disorder characterized by low peak GH levels during provocative tests. The AGHD has a negative impact on bone mineral density, skeletal muscle strength, physical capacity and psychosocial well-being [1]. Furthermore, this endocrinopathy disturbs the female reproductive system resulting in infertility [2, 3]. Treatments for AGHD with GH replacement therapy has been officially approved since 2006 in Japan. The clinical symptoms of AGHD above should be alleviated with this therapy. We encountered a 28 year-old female patient with AGHD who conceived a child during GH replacement
Received Jul. 12, 2010; Accepted Oct. 8, 2010 as K10E-208 Released online in J-STAGE as advance publication Oct. 30, 2010

therapy. Therapy was suspended at the 8 week of pregnancy. The patient delivered a healthy baby after a full-term pregnancy. We further describe this case, as there is little report of Japanese patients regarding the role and safety of GH replacement therapy during early pregnancy.

Case Report
The patient was diagnosed as pituitary dwarfism at age 9. She was treated with subcutaneous injections of GH since diagnosis until her height reached 155cm at age 15. At age 24, psychotropic medications were initiated to treat dysthymic disorder. She was hospitalized for treatment of an eating disorder and depression 3 times during a period for two years since age 25. She also suffered from clinical symptoms relating to GH deficiency: obesity, depression, poor concentration and dysmenorrhea an irregular menstrual cycle of about

Correspondence to: Takanobu Wakasugi, M.D., Department of Endocrinology and Metabolism, Fukui Prefectural Hospital, 2-8-1, Yotsui, Fukui-shi, Fukui 910-8526, Japan. E-mail: takunem@mist.ocn.ne.jp
The Japan Endocrine Society

66

Sakai et al.

1.5 months, short menstrual duration of 2-3 days, and small amount of menstrual bleeding. Her dysmenorrheal complaints might be also related to psychological mood and medicine. At age 26 years 10 months, she visited our hospital for reintroduction of GH replacement therapy to alleviate these clinical symptoms. She has been treated with the GH replacement since then. Her physical findings before GH replacement therapy were as follows: height 157.9cm, weight 58.8kg, BMI (Body mass index) 23.6 kg/m2, waist circumference 89.5cm, hip circumference 92.5cm, blood pressure 92/55mmHg. There were no abnormal findings in chest, abdomen or extremities. Her laboratory data were as follows: aspartate aminotransferase 57 IU/L (reference range, 6-43), alanine aminotransferase 39 IU/L (11-33), -glutamyl transpeptidase 43 IU/L (9-32), total cholesterol 251 mg/dL (130-220), high density lipoprotein cholesterol 64 mg/dL (40-65), low density lipoprotein cholesterol 165 mg/dL (60-140) and triglyceride 110mg/dL (50-150). Other laboratory test results (including red and white blood cell counts, platelet cell count, serum levels of electrolytes, glucose, total protein, albumin, globulin, bilirubin, creatine kinase, creatinine and uric acid) were normal. Serum GH was 0.12 ng/mL (0.28-1.64), and serum IGF-I 96 ng/mL (119-389). Serum GH and IGF-I levels were measured by immunoradiometric assay using a commercial kit Daiichi (TFB INC, JAPAN). Other endocrine hormones were within reference range (Table 1). In addition, no abnormal finding was found in the pituitary by the diagnostic MR imaging. No abnormal episode was reported during perinatal period of the GH-deficient patient. She was suffered from neither brain tumor nor brain trauma. Her parents were not short stature. No genomic examination was performed. We considered that she had been suffering from idiopathic isolated GH deficiency since childhood.
Table 2 Glucagon provocative test
Time (min) GH (ng/mL) 0 0.09 30 0.11 60 0.17

Table 1 Endocrinological data of the first medical examination

GH IGF-I LH FSH estradiol progesterone PRL ACTH Cortisol TSH free thyroxine free triiodothyronine 0.12 ng/mL 96 ng/mL 3.15 mIU/mL 5.54 mIU/mL 26 pg/mL 0.13 ng/mL 11.61 ng/mL 26 pg/mL 12.8 g/dL 2.56 IU/mL 0.96 ng/dL 2.8 pg/dL

Diagnosis of AGHD was confirmed by two provocative tests with separately loaded glucagon and GHRP-2 (Tables 2, 3). GH replacement therapy was reintroduced with subcutaneous injections of Humatrope 0.2mg (0.021mg/kg/w58.8kg=1.2mg/w) bedtime daily on weekdays (Fig. 1). The patients dysmenorrhea improved 3 months after reintroduction of GH replacement therapy. No obvious side effects or blood test abnormalities were observed. There were several short intermissions of GH injection because of economical reason (Fig. 1). We advised the patient against conception during replacement therapy because the safety of the commercially available GH injections for pregnant women has not been fully confirmed yet. However, she was found to be 8-weeks pregnant at age 28 years 7 months. We immediately ceased replacement therapy and carefully observed the patient with monthly measurements of serum GH and IGF-I levels. Serum GH levels fell immediately with cessation, and kept low levels throughout pregnancy. Serum IGF-I levels were elevated during the second half of pregnancy, and

90 0.21

120 0.69

150 0.48

180 0.29

Peak value of serum GH should be less than 1.8ng/mL in subjects with severe adult GH deficiency (AGHD). Table 3 GHRP-2 provocative test
Time (min) GH (ng/mL) 0 0.12 15 4.19 30 4.75 45 2.89 60 1.61

Peak value of serum GH should be less than 9ng/mL in subjects with severe adult GH deficiency (AGHD).

AGHD woman during GH therapy bore a baby

67

Fig. 1 Change of IGF-I level from the beginning of replacement therapy through 8th week of the patients pregnancy. Just after turning 27 years old, the patient discontinued therapy for 10 days. GH was injected every other month since age 27 years 8 months for four months because of economical reason. Since then, she felt able to afford it on a continuous basis.

Fig. 2 Change of serum IGF-I and GH during pregnancy and after delivery. Serum GH levels fell immediately after cessation of GH therapy, and kept low values throughout pregnancy. Serum IGF-I levels increased during the second half of pregnancy and fell within 12 hours of delivery.

68

Sakai et al.

decreased within 12 hours of delivery (Fig. 2). She delivered a healthy girl at 40 weeks of pregnancy: the babys Apgar score was 9/10 points, weight was 3442g, and the baby was without any congenital deformities. The mother was able to breastfeed the baby, and GH replacement therapy was reintroduced the day following delivery (Fig. 2).

Discussion
The dysmenorrhea of our case improved after GH therapy for AGHD. The patient became pregnant during regular GH injection. Then we considered that GH replacement therapy was effective for fertility. Although GH replacement therapy was continued through the early stage of pregnancy, no recognizable side effects were observed in neither mother nor fetus. To our knowledge, there are no other reports of a Japanese patient becoming pregnant during GH replacement therapy, and few cases have been reported in other countries [3-5]. Wirn L, et al. reported 12 pregnancies in 8 female patients with hypopituitarism. GH administration doses of Wirns cases was maintained at pregestational doses during the first trimester, with a gradual decrease during the second trimester and followed by discontinuation at the beginning of the third trimester. No major side-effect and no negative influences on maternal or fetal outcomes were observed [4]. Giampietro A, et al. reported 4 AGHD female patients with long-durational infertility who received GH therapy for 6-12 months until pregnancy

was confirmed. All had uneventful pregnancies, fullterm deliveries and healthy babies with normal stature in length and weight. These reports and our experience suggested the safety of GH therapy during early stage of pregnancy. Spiliotis BE suggested GH/IGF-I influences the pituitary and gonadal functions causing problems in the reproductive ability [3]. Giampietro A, et al. mentioned the important roles of GH and IGF-I regulations on oocyte fertilization in the early stage of the pregnancy [5]. These reports suggest that regular GH injection in our patient improved oocyte fertilization resulting in pregnancy. Mller J, et al. reported GH therapy prevent a pregnant woman with GH difficiency from having a miscarriage [6]. On the other hand, Curran AJ, et al. reported that the GH replacement therapy was dispensable for successful outcome in 16 female patients with AGHD [7]. Another report indicated a causative relationship between GH replacement therapy and polycystic ovary [8]. It remains uncertain whether the therapy is safe and essential for fetal development, fertility, and continuation of pregnancy in AGHD subjects.

Conclusion
We herein reported a case of 28 year old Japanese female patient with AGHD who inadvertently continued GH replacement therapy until the 8th week of her pregnancy. She and her baby showed no obvious side effects throughout pregnancy and delivery.

References
1. Fukuda I (2009) Diagnosis of adult GH deficiency: Horumon To Rinsho (Clin Endocrinol(Tokyo)) 57(4): 59-65 (in Japanese). 2. Overton CE, Davis CJ, West C, Davis MC and Conway GS (2002) High risk pregnancies in hypopituitary women. Hum Reprod 17(6): 1464-1467. 3. Spiliotis BE (2003) Growth Hormone Insufficiency and Its Impact in Ovarian Function. Ann N Y Acad Sci 997: 77-84 4. Wirn L, Boguszewski CL, Johannsson G (2002) Growth hormone (GH) replacement therapy in GH-deficient woman during pregnancy. Clin Endocrinol (Oxf) 57(2): 235-239. 5. Giampietro A, Milardi D, Bianchi A, Fusco A, Cimino V, Valle D, Marana R, Pontecorvi A, De Marinis L (2009) The effect of treatment with growth hormone on fertility outcome in eugonadal women with growth hormone deficiency: report of four cases and review of the literature. Fertil Steril 91(3): 930.e7-e11. 6. Mller J, Starup J, Christiansen JS, Jrgensen JO, Juul A, Skakkebaek NE (1995) Growth hormone treatment during pregnancy in a growth hormone-deficient woman. Eur J Endocrinol 132: 727-729. 7. Curran AJ, Peacey SR, Shalet SM (1998) Is maternal growth hormone essential for a normal pregnancy? Eur J Endocrinol 139: 54-58. 8. Tsilchorozidou T, Conway GS (2004) Uterus size and ovarian morphology in women with isolated growth hormone deficiency, hypogonadotrophic hypogonadism and hypopituitarism. Clin Endocrinol(Oxf) 61: 567572.