Patients, Materials, and Methods
In this prospective study, we evaluated five patients with childhood-onset CPHD who requested fertility treatment. They were all diagnosed in childhood with severe short stature; the diagnosis was based on failure to have a normal response to combined pituitary stimulation test (0.05–0.1 U/kg insulin, 200 μg thyrotropin-releasing hormone, and 100 μg gonadotropin-releasing hormone, intravenously) and/or low basal IGF-1, IGF binding protein 3, free thyroxine, LH, FSH, estradiol or testosterone, and cortisol levels. IGF-1 levels were measured using an immunometric assay (IMMULITE 2000; Siemens Health Care Diagnostics, Llanberis, Gwynedd, United Kingdom). Magnetic resonance imaging scans were performed in a 1.5 Tesla unit (Sigma; GE, Milwaukee, WI) using T1- and T2-weighted sagittal and coronal scans.
These five women made up the first set of patients with CPHD referred to this infertility care unit. For comparison purposes, we report the overall pregnancy rates achieved by women being treated for other infertility factors besides CPHD during the same period of this study and at the same facility.
B. Basic Infertility Workup
All women underwent a basic infertility workup consisting of hysterossalpingography, serum determinations of LH, FSH, and estradiol, transvaginal ultrasound for AFC, and uterine morphology assessment. Three patients had also serum AMH determination. All male partners underwent semen analysis.
C. Fertility Treatment
Patients with no other identifiable infertility factor than anovulation (HH) were submitted to controlled ovarian stimulation (COS) for timed intercourse (TI). Couples in which a mild male factor (altered semen analysis but ≥5 million motile sperm and >4% normal sperm according to strict morphology criteria) was identified were submitted to COS and intrauterine insemination (IUI). When a tubal abnormality or severe male factor (<5 million motile sperm or ≤4% strict morphology in at least two semen analyses) was identified or when couples had three consecutive failures of TI/IUI, they were offered in vitro fertilization (IVF).
COS was performed with human menopausal gonadotropin (Menopur; Ferring Pharmaceuticals, Kiel, Germany), containing both FSH and LH activity (1:1). Daily subcutaneous gonadotropin administration started between menstrual cycle days 3 through 7. The initial dose varied from 75 IU/d (TI and IUI) to 150 IU/d (IVF). Patients were subjected to transvaginal ultrasound scans on stimulation days 5 and 6 and every 2 to 3 days after that; at each examination, the endometrial thickness and the mean diameter of each ovarian follicle were recorded. If after 7 days of stimulation there were no follicles ≥10 mm in mean diameter, the daily human menopausal gonadotropin dose was increased in 75 IU. Cycles were canceled when there was no follicle ≥10 mm after 14 days of stimulation or no follicle ≥15 mm after 28 days of stimulation. When the leading follicle reached >18 mm in mean diameter, 250 μg of recombinant hCG (Ovidrel; Merck, Bari, Italy) were administered, and TI, IUI, or transvaginal ultrasound–guided follicle aspiration was performed 36 hours later according to each patient's treatment protocol.
Gamete processing, fertilization, and embryo culture and transfer to the uterus proceeded as previously described. Elective single-embryo transfers (eSETs) were performed in all IVF cycles. Also, because multiple pregnancies were associated with poor prognosis in women with CPHD, when COS for TI or IUI resulted in more than one growing follicle, the treatment was converted to IVF and eSET to reduce the risk of multiple gestation. All embryos were transferred at the blastocyst stage. When more than one viable embryo was obtained, the extra embryos were cryopreserved (vitrification).
Patients undergoing IVF or IUI received luteal-phase support with vaginal micronized progesterone (400 mg/d in IUI and 600 mg/d in IVF). When frozen-thawed embryo transfer was required, patients had endometrium preparation with oral estradiol valerate (6 mg/d) from menstrual cycle day 3 on. Transvaginal ultrasound was performed weekly, and, when the endometrial thickness reached ≥7 mm (after at least 10 days of estradiol valerate), micronized progesterone was added to the regimen (600 mg/d, vaginally). Five days later, embryos were thawed (one at each transfer attempt) and transferred to the uterus. The remaining embryos were kept frozen.
Pregnancy was confirmed with serum β-hCG test 14 days after TI, IUI, or embryo transfer. The first obstetric transvaginal ultrasound, to confirm an intrauterine pregnancy, was performed 14 days after the initial positive β-hCG test.
J Endo Soc. 2017;1(10):1322-1330. © 2017 Endocrine Society