Successful pregnancy and delivery after ovulation induction therapy in a woman with congenital hypogonadotropic hypogonadism: a case report

CHH exhibits significant genetic heterogeneity, with only about 30% of cases having a familial link, while the vast majority are sporadic [8]. The epidemiological difference in prevalence between males and females remains unclear. CHH has various inheritance patterns, such as autosomal recessive and dominant, and X-linked recessive [8]. Rare ANOS1 variants, located on the X chromosome, account for around 10% of cases and are among the most prevalent genetic causes [9]. X-linked inheritance may explain the lower prevalence of CHH in females. Due to the difficulty in distinguishing CHH from other GnRH deficiencies, partial CHH in females may be underdiagnosed [4]. Here, we present the case of a woman with CHH who achieved a successful pregnancy and delivery following ovulation induction therapy.

Pulsatile secretion of GnRH is crucial for the development of secondary sexual characteristics and reproductive functioning in both sexes [10]. GnRH-producing neurons differ from other neuroendocrine cells in that they originate in the olfactory placode, migrate extensively during embryonic development, and finally settle in the hypothalamus region at birth [7]. As maternal hCG primarily drives the development of external genitalia, there are usually no abnormalities in the development of the internal and external genitalia in CHH females [11]. In addition, childhood can be considered a hypogonadal state due to the relative quiescence of the GnRH pulse generator, making early diagnosis challenging [4].

Puberty initiation is dependent on the activation of the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis is gradually reactivated, leading to an increase in GnRH secretion. Pulsatile GnRH release stimulates the synthesis and release of gonadotropins such as FSH and LH by pituitary. These hormones, in turn, stimulate the gonads to produce sex steroids and gametes [12]. Elevated estrogen levels promote uterine growth, breast development, and the onset of the menstrual cycle. GnRH deficiency results in incomplete or absent puberty development, with CHH females exhibiting varying degrees of breast underdevelopment, with over 90% of them experiencing primary amenorrhea [13]. Patients with no breast development or menstruation over the age of 15 are advised to undergo a thorough examination to obtain an accurate diagnosis [8]. Timely and appropriate hormonal replacement therapy (HRT) is critical for CHH female patients. HRT can induce puberty, maintain secondary sex characteristics, stimulate growth in stature, achieve peak bone mass, and promote patients’ psychosexual development. The patient in this report was diagnosed at 18 years old and received hormone replacement therapy. However, her pubertal development was suboptimal. Delaying estrogen replacement and administering an insufficient estrogen dose may have caused breast dysplasia and short stature. As a result, HRT must be handled with great care, and where feasible, such treatment should be supervised by a specialist since it must be customized for fertility treatment.

Inducing gonadotropins via GnRH is essential to produce gametes and achieving fertility. Based on the two-cell–two-gonadotropin theory [14], the synergistic effect of FSH and LH is critical for the normal development of follicles. FSH promotes the recruitment of secondary ovarian follicles in the ovarian antrum, regulates the development and atresia of follicles, while LH stimulates theca cells to produce androgens which are converted to estrogens in granulosa cells by FSH-induced aromatase [15]. LH is also necessary for optimal follicular development and ovulation. Due to GnRH deficiency, CHH females present impairment in follicular terminal growth and maturation. Therefore, ovulation induction treatment is required for these women to be able to conceive. Women with CHH require simultaneous ovarian and uterine priming due to chronic gonadotrophin deficiency. Ovarian priming is achieved with HMG or recombinant FSH and LH, while uterine priming is achieved with estrogen [6].

Ovulation can be achieved by pulsatile GnRH or gonadotropin stimulation. Pulsatile GnRH hormone pumping can restore the physiological secretion of pituitary gonadotropin, resulting in ovulation [16]. The pump is controlled by a microcomputer, with the dose and frequency of GnRH release able to be adjusted precisely [17]. The main advantage of this treatment is lower rates of multiples and ovarian hyperstimulation syndrome, but as it needs a special pump and continuous subcutaneous injections, it is not widely used. Gonadotropin stimulation followed by HCG to trigger ovulation is a more commonly used treatment option for inducing fertility in CHH patients. Gn is currently available in various formulas and usage methods and is commonly used in ovulation induction therapy.

In this report, the initial dose of HMG used for treatment was 75IU, which was increased to 150IU after six days. However, the cycle was canceled due to follicular dysplasia. In the second cycle, the treatment began with an initial dose of 150IU, and the follicles grew normally, but the estrogen level was low. An IVF treatment on an HH woman which confirmed that LH-free stimulation induces normal follicular growth accompanied by low E2 production and without normal oocyte maturation and fertilization ability [18]. The direct cause of poor oocyte quality was found to be insufficient LH secretion [18]. HMG contains LH and FSH in a ratio of 1:1, and typically, a daily HMG dose of 75 to 150 IU is sufficient to induce ovulation in CHH females. However, in this report, the patient had experienced multiple failed ovulation inductions with HMG doses ranging between 75 and 150 IU/d, suggesting that patients may require a higher LH threshold to achieve full maturation and ovulation of oocytes. In the third and final cycle of ovulation stimulation, recombinant LH was added based on the results of the previous treatment. After 12 days of ovulation, three mature follicles grew, and the estrogen levels remained normal. Follicular growth was significantly enhanced through LH supplementation, consistent with previous results [19, 20]. Studies with HH women have shown that the minimum LH level necessary for normal follicular growth in HH patients is debated, and personalized treatment with an optimal LH/FSH ratio is required according to the ovarian response [21, 22].

However, it is worth noting that in this report, HMG should have returned to a lower dose after supplementation with r-LH. In retrospect, a lower dose would have been more prudent, and perhaps the patient would not have eventually developed three mature follicles, which can also prevent multiple pregnancies. In a young woman in her very first opportunity to conceive, triggering 3 mature follicles may have been considered risky. It is also important to note that the patient had experienced multiple failed ovulation inductions (including several times at other hospital), and had a strong desire to attempt pregnancy. After fully explaining the possible risks, including multiple pregnancies and hyperstimulation syndrome, the patient chose to attempt pregnancy. While healthy twins ultimately resulted, this outcome could have been much more complicated. This report serves as a valuable lesson for clinicians to carefully consider risks and benefits of each treatment option for their patients.

CHH is a genetically heterogeneous disorder, with more than 30 gene mutations identified to date [23]. Oligogenicity has also been reported in CHH [23]. Patients with a positive family history should consider genetic counseling. In this report, the patient declined genetic testing, but we recommended genetic testing to determine the genetic origin of the disorder, enabling early assessment of offspring to ensure early diagnosis.

When dealing with women with CHH, a holistic approach is important, addressing not only fertility but also body image, psychosexual development, and relationship confidence [6]. Psychological and peer support should be strongly considered to address these issues [3, 24].

Overall, CHH is rare in females and it can be difficult to diagnose. Clinicians should pay attention to constitutional delays in growth and puberty, as early diagnosis and timely and appropriate hormone replacement therapy are important to increase uterine size and to promote psychosexual development which are ultimately important for future pregnancy. Ovulation induction therapy is necessary to stimulate fertility. Gn therapy is a feasible and effective treatment for reproduction in CHH females, but the selection of Gn type and dosage must be personalized to maximize fertility outcomes. Effective treatment is available not only for inducing estrogenization and promoting fertility, but also for addressing concerns about psychological and emotional well-being.