A total of 20 women of childbearing age with NC-21OHD who complained of infertility were included in this study. Of the 20 women, 87.5% were shown to have inappropriate progesterone elevation in the follicular phase as the earliest finding to diagnosis. Despite hormone therapy during the preconception and perinatal periods, the success rate of assisted reproduction or natural conception is still significantly lower in women with NC-21OHD than healthy women. Specifically, women with NC-21OHD are characterized by a low rate of conception and a high rate of spontaneous abortion, and nearly one-half of affected women give up pregnancy preparation due to an inadequate understanding of the genetic disease. Indeed, factors influencing the low fertility rate are not only NC-21OHD, but psychological and social factors. By reviewing the literature and summarizing GC treatment in the four women who delivered babies, it was found that the dose of GCs post-conception does not usually need to be increased.

The adverse effects of NC-21OHD-related hormone disorders on female fertility may be multifaceted and include the following: (1) a high androgen level interferes with the pulsatile secretion of GnRH or LH and inhibits ovarian follicular development; (2) there is co-localization of androgen and FSH receptors in granulosa cells, and a high androgen level affects the production of ovarian steroid hormones; (3) a high progesterone level thickens the cervical mucus, which is not conducive to sperm penetration; (4) a high progesterone level inhibits endometrial growth and affects endometrial receptivity; and (5) an elevated progesterone level inhibits tubal peristalsis, but also inhibits follicular development, thereby increasing the risk of infertility [6, 11,12,13, 27,28,29]. Nevertheless, most women with NC-21OHD are able to conceive naturally, so GC therapy is not recommended in asymptomatic non-pregnant NC-21OHD patients. In fact, studies have shown that 53–68% of women with NC-21OHD can conceive naturally before diagnosis and treatment [10, 11]. A multicenter study by Moran et al. [10] confirmed that of 203 pregnant women with NC-21OHD, 138 (68%) had a pregnancy before the diagnosis of NC-21OHD and 65 (32%) had a pregnancy after the diagnosis. Bidet et al. [11] reported that of 187 pregnancies in 190 women with NC-21OHD, 99 (52.9%) occurred before NC-21OHD was diagnosed (96/99 were natural pregnancies) and 88 (47%) pregnancies occurred after the diagnosis of NC-21OHD (11/88 were natural pregnancies). NC-21OHD is associated with lower gonadal damage than classical 21-OHD [30]. Therefore, the possibility of natural pregnancy in women with NC-21OHD is much higher than women with classical 21-OHD.

For women with NC-21OHD and excessive androgens, infertility, or a history of an abortion, GC treatment can shorten the time-to-conception and reduce the abortion rate [31]. Studies have confirmed that the risk of pregnancy loss in women with NC-21OHD after GC treatment is significantly lower than before treatment (26% vs. 6%) [10, 11]. A retrospective study in Israel included 75 infertile women with NC-21OHD, 72 of whom conceived (187 pregnancies). The time-to-pregnancy of the untreated group was 4.0 ± 7 months compared to 3.3 ± 3 months in the GC-treated group. After assisted conception, there were 17 pregnancies in women treated with GCs. The time-to-conception before treatment was 10.2 ± 11.4 months compared to 3.3 ± 3.4 months after treatment. Of the 187 pregnancies, 135 (72%) were live births, 38 (20.3%) were spontaneous abortions in the first trimester, seven (3.7%) were elective terminations, three (1.6%) were ectopic gestations, and four (2.1%) are under investigation. The study showed that there is no correlation between women with NC-21OHD who receive GC treatment and the abortion rate, but in NC-21OHD women who had failed to conceive without GC therapy, the time to conceive after they received it was significantly shorter [31]. Another retrospective study showed that of the 173 female patients with NC-21OHD, 78 had no pregnancy plans, 86 of 95 patients with a pregnancy plan had 176 pregnancies, and nine did not conceive. Of the patients, 56% were treated with GCs, 44% were untreated, and there were 128 live births in 76 patients. Of the patients treated with GCs, 66% had regular menstrual cycles and significantly lower levels of androgens and Prog, and the treatment was associated with a shorter duration of pregnancy. Androgen levels and duration of pregnancy were positively associated with pregnancy loss rates [32]. These studies suggest that GCs may be beneficial for conception among infertile women with NC-21OHD, and is often recommended before a pregnancy is contemplated. In this study, three women conceived naturally after taking GCs and all three gave birth to healthy babies.

High androgen levels are corrected by GC treatment alone and ovulation is restored. Anovulatory patients can treated with clomiphene or gonadotropins to induce ovulation [5, 6, 28, 33]. IVF-ET may be considered if the patient is not pregnant after the above treatment or in patients with tubal obstruction and/or endometriosis. To avoid the adverse effects of a high Prog level induced by ovulation induction on pregnancy, frozen-thawed embryo transfer can be performed at the best time [34, 35]. In this study one woman who did not conceive after GCs treatment successfully conceived by IVF-ET and one healthy baby was delivered. Searched by Pubmed, 10 case reports were included in present study, involving 13 NC-21OHD infertile women of childbearing age treated with GCs. Twelve women conceived after receiving GC treatment before pregnancy, including nine natural conceptions, two pregnancies after IVF-ET, and one pregnancy after ovulation induction.

Women with NC-21OHD who conceive without GC treatment do not need to receive GCs during pregnancy [34]. The early pregnancy loss rate is likely to be lower when patients are treated with GCs, so the continued use of GCs during pregnancy is recommended [36]. In some cases antenatal treatment failure can be attributed to the late start of treatment, an insufficient dose of GCs, and poor maternal tolerance leading to drug reduction or early withdrawal [37]. Commonly used GCs include DEX, Pred, and HC. The safety of DEX during pregnancy has not been determined [38]. DEX can inhibit the hypothalamus–pituitary–adrenal axis (HPA) of the fetus through the placenta and can effectively inhibit adrenal gland androgens in children with 21-OHD, avoiding masculinization of the female fetal external genitalia and reducing the need for reconstruction surgery. However, prenatal use of DEX may be associated with fetal developmental defects [3, 39, 40]、low birth weight [41]、decreased fetal length [42]、cognitive impairment [43], and may even permanently affect the expression of carbohydrate homeostasis-related genes that alter the normal effects of the HPA [44]. However, a 2019 meta-analysis concluded that prenatal DEX treatment reduced fetal masculinization in women at high risk for 21-OHD, with no significant differences in neonatal physical, cognitive, behavioral, or temperament outcomes [45]. At present, the prenatal application of DEX has not been established. To ensure that the risk-to-benefit ratio is minimized for pregnant women with NC-21OHD who are at high risk for a fetus with 21OHD and are considering prenatal treatment, it is recommended to use a program approved by the relevant institutional review committee with a large sample size for prenatal treatment. DEX treatment must be started nine weeks before pregnancy (reported in the literature seven weeks ago) to prevent fetal genital malformations or reduce clitoral hypertrophy in female fetuses [46, 47]. Combined with the cases in this report and the literature, the therapeutic dose of DEX ranges from 0.25 to 1 mg/d. Pred is sometimes more effective in establishing regular cycles and ovulation and can be used prior to conception [33]. Pred can also be used during pregnancy and Pred does not cross the placental barrier. Combined with the cases in this report and the literature, the therapeutic dose of Pred is between 2.5 and 7.5 mg/d, and can be combined with HC. HC is inactivated by placental 11βHSD2 and does not cross the placenta. After the initiation of HC treatment, most women with NC-21OHD (78%) became pregnant without ovulation induction [11]. The initial dose of HC is 10–60 mg/d, which can be combined with Pred. DEX crosses the placenta, so it is critical to use only HC and Pred for GC substitution during pregnancy to avoid adverse effects on the fetus.

In this study 20 women were treated with GCs, including 11 treated with HC, one treated with Pred, six treated with DEX, and two treated with HC combined with Pred. Four women with NC-21OHD who had delivered babies were all treated with HC before pregnancy was confirmed. The dose of HC during pregnancy was unchanged in three women and increased in one woman. Through Pubmed search, 10 case reports were included in present study, involving 13 NC-21OHD infertile women of childbearing age treated with GCs. 12 were treated with GCs before pregnancy, five were treated with DEX, four were treated with Pred, and three were treated with HC. After pregnancy, 11 women continued to receive GC treatment; two were treated with DEX, four were treated with HC, and five were treated with Pred. After pregnancy, the dose of GCs was reduced in one woman, not adjusted or similar in four women, and increased in three women. Current studies and the present study suggest that not all infertile women with NC-21OHD need to increase the dose of GC after conception, and some patients may not increase the dose of GCs or even reduce the dose. Another retrospective study also showed that the dose of GCs did not need to be increased after conception. The dose of HC was decreased significantly from 7.5 ± 3.8 mg in the first three months of pregnancy to 6.4 ± 3.3 mg in the 2nd trimester and to 5.5 ± 4.4 mg in the 3rd trimester [31]. This finding is in contrast to the Lo et al. [48] and Witchel et al. [5] studies. Some studies suggest that the dose of HC in early pregnancy does not need to be increased but increased by 25% ~ 40% (5–7.5 mg) from the 24th week of gestation [5, 25, 49]. Stress doses should be used during delivery [50]. There is still a lack of guidelines for GC treatment during pregnancy in women with NC-21OHD; how to adjust GCs during pregnancy needs to be further verified.

Women with NC-21OHD have a 1.4%-2.5% risk of having a child with classic 21-OHD and up to 14% risk of having a child with NC-21OHD [10, 11]. Offspring of women with NC-21OHD generally do very well in school [51]. To reduce the above risks, it is recommended that women with NC-21OHD should be genotyped for CYP21A2 before planning a pregnancy and their spouses should also be tested for the CYP21A2 gene. Using RT-PCR to analyze cell-free fetal DNA (circulating DNA) from maternal blood can determine fetal gender and the CYP21A2 genotype in the 6th week of pregnancy, which reduces unnecessary treatment. Unfortunately, none of the four women who delivered babies in this study underwent such testing, and therefore continued HC treatment during pregnancy and no offspring were diagnosed with 21-OHD.

There were some shortcomings in this study, such as a small sample size, more patients discontinuing pregnancy plans, observation of only a few cases during the entire course of pregnancy with respect to the GC dose, a lack of long-term follow-up of patients and their offspring. Relevant cases should be collected and analyzed to provide reference for endocrine management endocrinology and/or assisted reproduction.