Assisted reproduction treatment in women with hypopituitarism has been associated with fewer ovulatory cycles, prolonged stimulation duration until ovulation, lower pregnancy rates, and higher miscarriage rates compared with women with isolated HH, suggesting that deficiencies of pituitary hormones other than gonadotropins have a major adverse effect on infertility treatment success. Moreover, a tendency to poorer outcomes has been reported when hypopituitarism is diagnosed at a young age.
We present here the fertility outcomes of the largest case series from a single center of women with childhood-onset CPHD. In our cohort, all women ovulated and achieved pregnancy in one to five COS cycles; only two COS cycles had to be cancelled due to low response to stimulation, and there was only one miscarriage (subsequently, the same patient had a monochorionic twin pregnancy and live birth). The patients' young age at treatment may have contributed to the good outcomes observed, but adequate hormonal supplementation, particularly GH, might have also influenced the results of treatments. Indeed, in case reports, GH supplementation to women with acquired hypopituitarism (including GH deficiency) during COS has been shown to improve both ovarian response to stimulation[5,10,20] and endometrial growth. One previous study reported six patients who resemble ours (i.e., idiopathic CPHD); three of them became pregnant, and only one used GH replacement prior to fertility treatment.
Serum AMH concentration and the number of antral follicles identified in the ovaries during a transvaginal ultrasound at the beginning of a menstrual cycle (AFC) have been used to predict the ovarian response to COS in terms of oocyte yield. Sonntag et al. and Deubzer et al. observed reduced AMH levels in patients diagnosed at a young age with CPHD with very low or undetectable gonadotropin serum levels. The authors hypothesized that severe gonadotropin deficiency affects AMH production in granulosa cells. Therefore, AMH does not precisely reflect the ovarian follicular reserve, although a lower level indicates a poorer prognosis of infertility treatments in patients with hypopituitarism, particularly those with severely suppressed gonadotropins since an early age. Our findings are in agreement with this hypothesis. Three women in our series (patients 2, 3, and 5) had very low AFC levels considering their ages.[23,24] They also had markedly suppressed serum gonadotropin levels. However, whereas the AMH level was reduced in the serum of patient 2, in agreement with her AFC, in patient 3 the AMH level was normal, contrasting with her AFC. Of note, patient 3 was taking OCPs when she was evaluated before the infertility treatment; OCPs are known to interfere not only with basal gonadotropin levels but also with AFC and uterine volume. Patient 3 was the only one in this series with reduced uterine volume. Indeed, gonadotropin serum levels in patient 3 were higher upon CPHD diagnosis. Therefore, only two women in our series (patients 2 and 5) had severely suppressed gonadotropin levels from childhood and reduced ovarian reserve tests results concomitantly. Both of these patients had their first attempt of COS cancelled due to low ovarian response. However, subsequent attempts promoted follicular development, pregnancies, and live births. These observations suggest that, in women with CPHD, reduced ovarian reserve tests results might be associated with longer stimulation duration and probably with cancelled cycles before ovulation is reached, but they do not preclude pregnancy.
Placental growth hormone, also known as growth hormone variant, is encoded by GH2. Its concentration gradually increases during pregnancy and replaces the pituitary GH. In normal pregnancies, placental growth hormone concentrations correlate with IGF-1, and, even in one patient with hypopituitarism due to POU1F1 mutation, this pattern was maintained.[26,27] Nevertheless, some researchers advocate the use of GH in the first two trimesters in patients with GH deficiency because IGF-1 levels can be very low in these patients, and this approach has proven to be safe.[12,27,28] In the present study, we maintained the use of GH throughout the pregnancy, monitoring IGF-1 levels in four patients. Three patients were adherent to GH use and one patient refused the treatment. The latter patient remained with IGF-1 levels below −2SD throughout pregnancy, which is not in accordance with many reports in the literature, where IGF-1 levels steadily rise along the second and third trimesters.[12,27] In the patient with twin pregnancy, GH was discontinued in the third trimester due to IGF-1 levels above +2SD. The other two patients on GH replacement had IGF-1 levels in the normal range along all pregnancy.
High rates of obstetric complications are reported in pregnancies of women with hypopituitarism, including fetal malpresentation, small for gestational age neonates, postpartum hemorrhage, and a high rate of cesarean deliveries. Also, in one large study there were no survivors from four sets of twins, leading to a strict recommendation to avoid multiple pregnancies in these women. Against all odds, an elective single embryo transfer in our series resulted in a monochorionic twin gestation with a successful vaginal delivery. The only case of perinatal complications was one fetus with intrauterine growth restriction that presented with fetal distress and needed neonatal intensive care. There was one fetal malpresentation (breech lie), three cesarean deliveries, and no cases of postpartum hemorrhage. All six infants/toddlers are now healthy with no signs of hypopituitarism.
In summary, optimized hormonal replacement, including GH, in women with childhood-onset hypopituitarism resulted in successful pregnancies and healthy babies after individualized fertility treatment. Diminished ovarian reserve tests results should not preclude fertility treatment in these women.
ACTH, adrenocorticotropic hormone; AFC, antral follicle count; AMH, antimullerian hormone; COS, controlled ovarian stimulation; CPHD, combined pituitary hormone deficiency; DI, diabetes insipidus; eSET, elective single-embryo transfer; FSH, follicle-stimulating hormone; GH, growth hormone; GHRT, growth hormone replacement therapy; HH, hypogonadotropic hypogonadism; IGF, insulin-like growth factor; IUI, intrauterine insemination; IVF, in vitro fertilization; LH, luteinizing hormone; OCP, oral contraceptive pills; SD, standard deviation; TI, timed intercourse.
This work was supported by The National Council of Technological and Scientific Development–Brazil grants CNPq-PQ 305743/2011-2 (to B.B.M.), CNPq-PQ 307922/2013-8 (to I.J.P.A.), and FAPESP São Paulo Research Foundation 2015/26563-7 (to L.R.C.).
J Endo Soc. 2017;1(10):1322-1330. © 2017 Endocrine Society