Successful Pregnancies After Adequate Hormonal Replacement in Patients With Combined Pituitary Hormone Deficiencies

Fernanda A. Correa; Paulo H. M. Bianchi; Marcela M. Franca; Aline P. Otto; Rodrigo J. M. Rodrigues; Dani Ejzenberg; Paulo C. Serafini; Edmundo Chada Baracat; Rossana P. V. Francisco; Vinicius N. Brito; Ivo J. P. Arnhold; Berenice B. Mendonca; Luciani R. Carvalho


J Endo Soc. 2017;1(10):1322-1330. 

In This Article


A. Hormonal Replacement Before Fertility Treatment

All five patients were deficient for GH, LH/FSH, and TSH. Patient 2 also had adrenocorticotropic hormone (ACTH) deficiency and diabetes insipidus (DI), patient 3 had ACTH deficiency, and patient 4 had DI. Neuroimaging was abnormal in all of them (Table 1). The patients were treated for all deficiencies since first presentation (ages ranging from 9 to 12 years) with standard doses of levothyroxine, cortisone acetate, and desmopressin; patients were moved to prednisone after reaching adult height. GH replacement doses ranged from 0.33 to 0.50 μg/kg/d. The age of pubertal induction varied from 12 to 16 years using conjugated estrogen tablets and medroxyprogesterone acetate. Adult height varied from 140 to 165 cm. The genetic diagnosis could be established in only patient 1, who harbors a GLI2 (p.L788fsX794) loss-of-function mutation.[19] The clinical and radiological features of this cohort are shown in Table 1.

Once the desire to conceive was expressed, patients were referred to the infertility care unit, and their hormonal replacement regimen was optimized. GH was reinstituted or optimized (0.3 to 1.0 mg daily) in all patients prior to ovarian stimulation treatment. IGF-1 after GH optimization ranged from 129 to 224 ng/mL (normal range for age and sex, 109 to 358 ng/mL) (Table 2). Conjugated estrogen tablets and medroxyprogesterone acetate or oral contraceptive pills (OCPs) were replaced by a regimen of oral estradiol valerate (2 mg for 21 days) + levonogestrel (0.25 mg) in the last 10 days of menstrual cycle with a 7-day interval between cycles; patient 3 kept using OCPs (20 μg ethinyl estradiol and 75 μg gestodene). Patients were 25 to 37 years old at the beginning of infertility treatment (Table 2).

B. Basic Infertility Workup

Results of the basic infertility workup are presented in Table 2. Of note, three women (patients 2, 3, and 5) had very low AFCs for their ages. They also had severely suppressed basal serum LH and FSH levels.

Patients 1 and 5 had partners with mild alterations on semen analysis; therefore, they were initially submitted to IUI. The treatment protocol for patient 5 was converted to IVF due to multifollicular growth in the second and third COS attempts. Patient 4 had an associated tubal abnormality and proceeded to IVF. Patients 2 and 3 had no tubal abnormalities or associated male infertility; hence, they were offered TI. After three unsuccessful TI attempts, patient 3 was submitted to two IVF cycles.

C. Fertility Treatment and Outcome

Treatments were performed between July 2012 and April 2014; outcomes are summarized in Table 3. All women became pregnant. Patients 2 and 5 had their first COS attempts cancelled due to low ovarian response to stimulation. In IVF cycles, the number of retrieved oocytes varied between 3 and 10, resulting in one to three viable embryos for transfer in each cycle. Patient 4 had a singleton pregnancy after a fresh eSET. In patient 3, a frozen-thawed eSET resulted in a singleton pregnancy. Patient 5 had a spontaneous first trimester miscarriage after her first IVF and a monochorionic twin gestation after a frozen-thawed eSET. All other pregnancies were singleton.

While these women were treated (2012 to 2014), the overall pregnancy rates (per initiated cycle) at this infertility care unit were 12% (TI), 12.4% (IUI), and 24.4% (IVF).

D. Hormonal Replacement During Pregnancy: Outcomes and Puerperium Details

Hormonal replacement therapy was monitored during pregnancy. GH was not discontinued, with the goal to maintain IGF-1 levels in the normal range. IGF-1 monitoring was possible in four patients. Patients 1 and 3 achieved normal IGF-1 levels with doses of GH ranging from 0.33 to 0.5 mg/d. Patient 2 refused to use GH during pregnancy, and her IGF-1 levels remained below −2 standard deviation (SD) during all pregnancies. Patient 5 had a twin pregnancy. Her IGF-1 levels started to rise above +2SD during the second trimester, and GH was discontinued in the third trimester (Figure 1). Regarding the treatment of other pituitary deficiencies, patients 2, 3, and 5 had ACTH deficiency, and there was no need to adjust the doses during pregnancy (doses of prednisone ranged from 2.5 to 5.0 mg/d). Patients 2 and 4 had DI, and the previous replacement dosage was maintained throughout pregnancy. Patients 2 and 4 were on desmopressin nasal spray (10 μg twice daily). Free thyroxine levels were within the normal range before and throughout pregnancy. As expected, there were changes in levothyroxine replacement therapy: all patients but patient 2 had increases in their daily doses (Table 4). The doses were increased in the first trimester, and the average increase was 32%.

Figure 1.

Longitudinal evaluation of IGF-1 levels in four patients with CPHD during pregnancy. Patients 1, 3, and 5 were receiving GH replacement (dose ranging from 0.33 to 0.66 mg/d). Patient 2 did not receive GH treatment. IGF-1 normative reference values according to age and sex are shown by the gray area (109 to 358 ng/mL).

The gestational age at birth ranged from 35 to 39 weeks and 4 days. One fetus had breech presentation. There were three cesarean and two vaginal deliveries. The cesarean sections were indicated due to breech presentation (patient 1), labor dystocia (patient 2), and fetal distress (patient 4). Only patient 4 had a newborn small for gestational age (1650 g). This newborn needed orotracheal intubation for 24 hours and was discharged from the hospital 19 days after birth. This was the only case of perinatal complications. The other five newborns, including the twins, were born with adequate birth weight. Three patients were able to breastfeed (Table 4). All six infants/toddlers were healthy and had no signs of hypopituitarism.