Case 1
A 27-year-old female initially presented to our department in 2019 for recurrent cysts and an inability to become pregnant over a 5-year period. She had her first menarche at the age of 16, followed by irregular menstrual cycles. Without any further investigations, she was started on oral contraceptives, masking her symptoms. A salpingogram was then performed, revealing both fallopian tubes to be patent. Ultrasound-based monitoring of follicular development and detecting hormone levels revealed ovulation disorder and an unusual rise in progesterone(P4) levels to up to 19 nmol/L prior to ovulation, prompting further investigation. She was 158 cm tall, weighed 61 kg, had a body mass index (BMI) of 24.4 kg/m2, and an arterial blood pressure (BP) of 115/69 mmHg. Physical examination showed a Tanner stage IV-V breast development, sparse pubic hair, a feminine vulva, and a normal clitoris. Vaginal examination revealed a slightly smaller than average uterus, ovarian showed multiple follicular cysts and no lumps were palpable in the labia or groin. Given the patient’s history and presentation, hormone levels were next examined, with chemiluminescent immunoassays next being used to measure concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P4), testosterone (T), pituitary prolactin (PRL), dehydroepiandrosterone sulfate (DHEAs), androstenedione (AND), and 24-h urinary free cortisol(UFC). Moreover, radioimmunoassays were used to measure plasma renin activity(PRA), aldosterone(ALD), adrenocorticotropic hormone (ACTH), cortisol (COR), and 17 α-hydroxyprogesterone (17-OHP) levels, with 24 h urinary adrenaline(AD), norepinephrine(NRE), levels being measured simultaneously. These analyses revealed abnormally decreased AND, T, 17-OHP and COR levels together with elevated P4 and PRL levels. No abnormalities in FSH, LH, E2 and DHEAs or 24 h urinary free COR, ALD, AD, NRE, or dopamine(DA) levels were detected. The results are presented in Table 1. No abnormalities were detected on pelvic ultrasound, and left adrenal hyperplasia was detected via adrenal computed tomography (CT) imaging. The patient’s karyotype was 46,XX, and genetic diagnosis revealed the presence of the compound heterozygous missense variants c.887T > C(p.I296T) and c.1304T > C(p.F435S) in the CYP17A1 gene, consistent with a potential diagnosis of CAH as a consequence of partial 17-OHD. Her partner was also investigated and was found to have normal semen analysis. After learning about the condition, she wanted to achieve conception through natural pregnancy. In preparation for conception, the steroid replacement was prednisone 5 mg in the morning and 2.5 mg in the evening with targets being suppression of ACTH and P4 levels. She resumed regular menstruation and normal follicle development, two months after the prednisone dose was up titrated. On the fourth day of her menstrual cycle, she began follicular monitoring. On day 13 she had a dominant follicle in the right ovary. Since then, she showed further enlargement of the follicle. On day 18 she had a mature follicle, and on day 19 the mature follicle had collapsed, which was consistent with ovulation(Table 2). During the periovulation period, intercourse was performed. The patient ultimately achieved a natural pregnancy, giving birth to a live female newborn (3,250 g, 47 cm in length) at the gestational age of 39 weeks and 4 days.
Table 1
Clinical characteristics and hormonal profiles of the two partial 17α-hydroxylase deficiency cases.
| P1 | P2 | Normal value |
Age (y) | 27 | 32 | |
BP(mmHg) | 115/69 | 127/81 | |
FSH (IU/L) | 6.54 | 4.69 | 3.5–12.5 |
LH (IU/L) | 9.69 | 4.02 | 2.4–12.6 |
E2(pmol/L) | 224.8 | 408.2 | 45.4−854.8 |
P4(nmol/L) | 19.18 | 16.74 | 0.18–2.84 |
T(nmol/L) | < 0.09 | < 0.09 | 0.29–1.67 |
PRL(mIU/L) | 1272 | 741.4 | 102–636 |
17OHP(ng/mL) | 0.4 | 0.33 | 0.4–1.02 |
DHEA-S(µg/dL) | 47.9 | 25.7 | 35–430 |
AND(ng/mL) | < 0.3 | < 0.3 | 0.3–3.3 |
COR(8 am)(ng/mL) | 85.1 | 132 | 171–536 |
COR(4 pm)(ng/mL) | 61.3 | 90.7 | 64–327 |
ACTH (8 am)(pg/mL) | 141 | 76.5 | 7.2–63.3 |
ACTH (4pm)(pg/mL) | 56.3 | 10.4 | 4–32 |
PRA(laying)(ng/ml.h) | / | 0.34 | 1.5–6.9 |
PRA(standing)(ng/ml.h) | / | 2.46 | 0.2–1.9 |
Ang II (laying)(pg/mL) | / | 46.3 | 28.2–52.2 |
Ang II(standing)(pg/mL) | / | 56.46 | 55.3−115.3 |
ALD(laying)(pmol/L) | / | 474.53 | 134.6−342.6 |
ALD(standing)(pmol/L) | / | 585.36 | 173.9−663.9 |
24 h UALD(µg/d) | 1.8 | 2.4 | 1–8 |
24 h UFC (nmol/d) | 200 | 226 | 73–372 |
24 h UNRE(µg/d) | 42 | 34 | 0–50 |
24 h UAD (µg/d) | 13 | 10 | 0–20 |
24h UDA(µg/d) | 304 | 240 | 0−500 |
Abbreviations: BP,blood pressure; FSH, follicle stimulating hormone;E2, estradiol; LH, luteinizing hormone;P4, progesterone;T, testosterone;PRL,prolactin;17OHP,17-hydroxyprogesterone;AND, androstenedione;DHEA-S,sulfated dehydroepiandrosterone;COR,cortisol; ACTH,adreno-cortico-tropic-hormone; PRA,plasma renin activity; Ang,Angiotensin;ALD,Aldosterone;UFC,urinary free cortisol;UNRE,urinary norepinephrine; UAD, urinary adrenaline; UDA,urine dopamine. |
Table 2
Transvaginal sonographic findings, serum hormone levels, and treatments performed of the patient 1.
Menstrual cycle | Follicle size (mm) | Hormones (reference values) | Treatment |
Rt | Lt | LH (IU/L) fp 2.4–12.6 mc 14-95.6 lp 1.0-11.4 | E2 (pmol/L) fp 45.4-854.8 mc 151–1461 lp 81.9–1251 | P4 (nmol/L) fp 0.18–2.84 mc 0.38–38.1 lp 5.82–75.9 |
4 | 7 | 5 | | | | |
13 | 11 | 7 | | | 2.19 | |
16 | 14 | 7 | | | | |
17 | 16 | 7 | | | | |
18 | 18 | 7 | | | | intercourse |
19 | — | — | 19.63 | 272.8 | 6.94 | intercourse |
Abbreviation:fp, follicular phase; mc, mid-cycle; lp, luteal phase (in premenopausal women) |
Case 2
In 2019, a 32-year-old woman (46,XX) presented to our hospital due to menstrual disorders and an inability to conceive. This patient initiated puberty spontaneously and then developed oligomenorrhea. She was intermittently treated with estrogen progesterone treatment. She was 157 cm in height, weighed 58 kg, had a BMI of 23.5 kg/m2, and exhibited an arterial BP of 127/81 mmHg. She exhibited relatively sparse axillary and pubic hair for her age, but gynecological examinations did not reveal any abnormalities of the vagina or external genitalia. Enlarged polycystic ovaries were detected through transvaginal ultrasonography. As salpinography revealed the obstruction of the bilateral fallopian tubes, the patient was referred to undergo in vitro fertilization (IVF) as a form of assisted reproductive technology (ART). The women underwent standard controlled ovarian hyperstimulation (COH) with a downregulation protocol using a Gonadotropin-releasing hormone (GnRH) agonist protocol according to the patients' characteristics, serum hormone levels and transvaginal ultrasonography were used to monitor the development of ovarian follicles. The patient continued to receive daily injections of recombinant FSH (rFSH) (Gonal-F®, Merck Serono, Geneva, Switzerland), human menopausal gonadotropin (HMG) (Menopur, Ferring Pharmaceuticals) and/or recombinant LH (rLH)(Luveris1, Merck Serono Australia, Frenchs Forrest) were added according to follicle development, until a minimum of 3 follicles > 18 mm in diameter were evident, at which time she was administered 250 mg of recombinant human chorionic gonadotropin (r-HCG, Ovidrel, Merck Serono, Germany), with transvaginal oocyte retrieval being conducted 36 h post-injection. Hormone findings in the context of this ART treatment regimen are compiled in Table 3. This approach led to the retrieval of 17 oocytes, of which 14 were successfully fertilized, with two high-quality cleavage-stage embryos undergoing cryopreservation whereas the remaining embryos were cultured to the blastocyst stage, yielding 5 blastocytes. Persistent increases in serum P4 levels were observed throughout the process of ovarian stimulation (11.99–32.19 nmol/L). Abnormally high P4 levels have been linked to poorer implantation rates, and as a result, all embryos were cryopreserved and the patient underwent further diagnosis and treatment in the Endocrinology Department for diagnosis and treatment. Hormone tests revealed reduced T, 17-OHP, AND, COR and DHEAs levels together with elevated P4 and PRL levels. No abnormalities in FSH, LH, E2, ACTH or 24 h urinary free COR, ALD, AD, NRE, or DA levels were detected. The results are presented in Table 1.Biochemical laboratory test results were as follows: 24 h urine output 1.63 L; 24 h urinary potassium 38.72 mmol/24h; 24 h urinary calcium 2.22 mmol/24h; 24 h urinary chloride 129.08 mmol/24h; 24 h urinary sodium 130.88 mmol/24h; 24 h urinary phosphorus 13.30 mmol/24h. Genetic analysis revealed the presence of the compound heterozygous c.1396G > A(p.E466K) and c.1459-1467del(p.Asp487-Phe489del) variants in the CYP17A1 gene, with the former being identified for the first time and predicted to be pathogenic by both Mutation Taster and PolyPhen-2 analyses, while the latter has been confirmed to be pathogenic in prior literature reports(9). These genetic results were consistent with the diagnosis of CAH as a result of partial 17-OHD. Following definitive diagnosis, adrenal progesterone production was suppressed via the administration of oral prednisone (2.5 mg in the morning and 5 mg in the evening), with serum P4 levels falling to 3.34 nmol/L after 3 months. Endometrial preparation was then initiated using oral estradiol valerate (Progynova, Delpharm Lille SAS, France) (6 mg/d). When transvaginal ultrasonography on day 19 of the preparation process revealed that the endometrium had achieved a thickness of 7 mm, and luteal phase support was added with vaginal progesterone gel (Crinone, Merck Serono, Watford, UK)) 90 mg daily and oral dydrogesterone (Duphaston, Abbott, OLST, Netherlands) 10 mg twice daily. The clinical data during hormone replace treatment(HRT) are shown in Table 4.Then, 5 days later, a cryopreserved blastocyst was transferred into the uterus. On day 14 post-transfer, positive β-humanchorionic gonadotrophin (β-hCG) test results were obtained, with transvaginal ultrasonography confirming a singleton pregnancy at the gestational age of 6 weeks. The patient ultimately gave birth to a normal female newborn (3400 g, 45 cm in length) via cesarean section at the gestational age of 40 weeks and 3 days. The puerperium was uneventful, and the newborn was discharged home in good condition.
Table 3
Ovarian stimulation for IVF and the changes of hormones of the patient 2.
Cycle day | 3 | 33 | 37 | 40 | 42 | 44 | 45 |
Prednisone | 7.5mg/d | | | | | | |
Long-acting triptorelin (mg) | 3.75 | / | / | / | / | / | / |
rFSH (IU/d) | | 150 | 150 | 150 | 150 | 75 | |
HMG (IU/d) | | | 37.5 | 75 | 75 | 150 | |
rLH(IU/d) | | | | 75 | 75 | 75 | |
rHCG(µg) | | | | | | | 250 |
HCG (IU) | | | | | | | 2000 |
Follicles (mm) and (number) | 5(3),4(4),3(14) | 5(2),4(2),3(8),2(10) | 8(2),7(3),6(6),5(6) | 12(2),10(5),9(2),7(7) | 15(4),14(4),12(5),10(2) | 18(5),16(4),14(5),12(1) | 21(2),19(2),16(5),14(6),12(5) |
Endometrial thickness (mm) | 4.9 | 3 | 3.1 | 5.1 | 5.3 | 6 | 6.3 |
FSH (IU/L) | 4.96 | 0.89 | | | | | |
LH (IU/L) | 4.02 | 2.59 | | < 0.1 | 1.11 | 1.54 | 1.5 |
E2(pmol/L) | 408.2 | 18.70 | 106.7 | 205.8 | 761.4 | 1817 | 2361 |
P4(nmol/L) | 16.74 | 18.36 | | | 11.99 | 32.19 | 19.78 |
Abbreviation: rFSH,recombinant FSH;HMG,human menopausal gonadotropin;rHCG,recombinant human chorionic gonadotrophin. |
Table 4
Clinical data of the patient 2 during HRT.
Cycle day | 3 | 10 | 15 | 18 | 21 | 22 |
Endometrial thickness (mm) | 5 | 5.6 | 6.2 | 6.5 | 6.5 | 7 |
Follicles (mm) | 4 | 4 | 4 | 5 | 5 | 5 |
E2 (pmol/L) | 146.1 | / | 651.1 | / | 963.1 | / |
P4 (nmol/L) | 3.34 | 4.42 | 0.66 | / | 1.47 | / |
Medication | | | | | | |
Ethinyl oestradiol(mg/d) | 6 | 6 | 6 | 6 | 6 | 6 |
Natural micronized progesterone(mg/d) | / | / | / | / | / | 600 |
Prednisone(mg/d) | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 | 7.5 |