Kallmann-De Morsier syndrome is defined by the coexistence of anosmia (an olfactory deficit) and hypogonadism. The hypogonadism results from a deficiency of gonadotropin-releasing hormone (GnRH), a hypothalamic hormone that regulates pubertal gonadal development via the pituitary gland. The condition is four times less prevalent in girls than in boys, with an incidence of approximately 1 in 10,000 boys and 1 in 50,000 girls [1]. Most cases occur sporadically, but in familial forms, three modes of inheritance have been described: X-linked recessive, autosomal dominant, and, more rarely, autosomal recessive. Treatment consists of hormone replacement initiated at puberty, followed by ovulation induction to achieve fertility. Here, we present the case of a patient with Kallmann-De Morsier syndrome in whom ovulation induction therapy resulted in pregnancy.

Kallmann syndrome, first described by Franz Josef Kallmann in 1944, is a genetic disorder defined by the association of hypogonadotropic hypogonadism with anosmia or hyposmia. In his initial publication, Kallmann reported three families showing a consistent pattern of delayed puberty and absence of smell, and also described associated features such as mirror movements (synkinesia), skeletal anomalies (including syndactyly and craniofacial asymmetry) midline defects (such as cleft lip or palate), urogenital abnormalities (including renal agenesis and vesico-ureteral reflux), dental agenesis, intestinal malrotation, congenital cardiac anomalies, and neurological impairments such as central deafness and cerebellar ataxia. Based on this constellation of findings, Kallmann was the first to propose a genetic etiology for the disease [2].

In 1954, de Morsier reviewed multiple cases and described the association between hypogonadism and the complete or partial absence of the olfactory bulbs and tracts. The syndrome is now understood to arise from a developmental defect affecting both the olfactory system and the embryonic migration of GnRH-secreting neurons. Kallmann syndrome remains rare in women, possibly contributing to underdiagnosis [3]. The disorder is typically identified during adolescence due to absent or incomplete pubertal development. In our case, the patient presented with primary amenorrhea and hyposmia.

The diagnosis is based on clinical suspicion, confirmed by endocrine and imaging evaluations. Hormonal assessment reveals hypogonadotropic hypogonadism, characterized by low serum estradiol and low or inappropriately normal levels of gonadotropins (FSH and LH). Our patient’s profile showed a markedly reduced estradiol level with FSH and LH at the lower end of normal. MRI is essential for diagnosis, as it enables direct visualization of the olfactory bulbs and tracts above the cribriform plate. In our case, MRI confirmed the absence of olfactory bulbs, consistent with the diagnosis of Kallmann syndrome [4].

At the molecular level, six genes have been implicated in Kallmann syndrome: KAL1, FGFR1, FGF8, CHD7, PROKR2, and PROK2. However, the sensitivity of genetic testing is only about 30% [3], highlighting the continued importance of clinical diagnosis. The KAL1 gene, responsible for the X-linked form, was mapped to the Xp22.3 region and was one of the first genes identified in familial cases [2].

Fertility is a significant concern for women with Kallmann syndrome, as spontaneous ovulation is typically absent due to gonadotropin deficiency. Since 1970, only 24 pregnancies have been reported in women with confirmed Kallmann syndrome. Ovulation induction is therefore necessary, with several therapeutic strategies available, including pulsatile GnRH infusion, human menopausal gonadotropin (hMG), and recombinant gonadotropins such as FSH, often combined with LH or hCG [1].

Exogenous human FSH, either urinary-derived or recombinant (follitropin α, β, δ), plays a central role in ovulation induction and has been widely used in both anovulatory patients and in controlled ovarian stimulation protocols for in vitro fertilization [5]. Recombinant FSH (rFSH), delivered via pen-injector, offers advantages such as ease of use, dosing accuracy, and patient autonomy. Our patient received daily subcutaneous injections of rFSH starting on day 2 of her cycle at a dose of 62.5 IU, administered with a pen injector device. Follicular monitoring on day 13 demonstrated a dominant follicle measuring 19 mm and three additional follicles under 10 mm. Ovulation was triggered with recombinant hCG, followed by intrauterine insemination 36 hours later.

Several studies have compared different gonadotropin protocols in women with hypogonadotropic hypogonadism. Some authors recommend combining FSH and LH to optimize follicular development and estradiol production. For example, Nakagawa et al. [1] observed that ovulation induction with FSH alone may lead to suboptimal estradiol levels, fewer mature follicles, and reduced ovulation rates. They concluded that both FSH and LH are needed to achieve a satisfactory ovarian response in women with Kallmann syndrome [1,6].

Heraud et al. [2] used urinary hMG (containing both FSH and LH) for stimulation and recombinant hCG for ovulation triggering. In their case report, the patient developed a triplet pregnancy, underscoring the high sensitivity of these patients to gonadotropins and the importance of careful follicular monitoring. They concluded that while LH is not strictly required for folliculogenesis, it is critical for estradiol synthesis. However, assessment of biologically active LH can be challenging, especially after use of GnRH analogs [2].

Sullivan et al. [7] performed a controlled study in 24 patients pretreated with GnRH analogs. FSH alone was used to initiate follicular growth up to 14 mm, after which patients were randomized to continue with FSH alone, LH alone, or both. The results showed that estradiol production could be sustained by either hormone individually, though not always to the same extent [7]. Shoham et al. [8] similarly demonstrated that LH alone produced significantly fewer mature follicles than FSH alone or FSH with LH, reinforcing the pivotal role of FSH in achieving full follicular development.

A large prospective observational study involving 370 French gynecologists examined the use of rFSH delivered by pen-injector in 1,398 patients undergoing ovarian stimulation for either timed intercourse or intrauterine insemination. The study identified three main factors associated with pregnancy success: age under 35 years, a history of treatment-induced pregnancy, and the presence of ovulatory dysfunction [9]. Our patient fulfilled at least one criterion (ovulatory dysfunction) and achieved pregnancy after a single cycle of stimulation.

Other case series provide additional context. Zhao et al. [10] reported five women with Kallmann syndrome treated with gonadotropins (FSH and hCG). Despite variable ovarian responses and required dose adjustments, two pregnancies were achieved. This study highlighted the need for close monitoring due to the risk of ovarian hyperstimulation syndrome [10]. Castets et al. [6] described three women treated with daily rFSH followed by hCG; all demonstrated a good ovarian response, but only one achieved pregnancy after three cycles, suggesting that while ovulation is attainable, pregnancy may depend on multiple factors beyond the hormonal protocol alone.

Our case is consistent with these findings. The patient underwent controlled ovarian stimulation with rFSH at a low dose, followed by ovulation triggering with recombinant hCG, and achieved a successful pregnancy via IUI. This case confirms that fertility is possible in women with Kallmann syndrome, but requires individualized protocols, regular monitoring, and sometimes multiple cycles to achieve success.

In conclusion, hypogonadism is a medical condition defined by low production of sex hormones—principally testosterone in men and estrogen in women. While advances have been made, several areas of research are promising for the future. (1) Improved hormone replacement therapies, including sustained-release systems such as implants or transdermal formulations [11]. (2) Gene therapies: genetic modification may 1 day enable endogenous hormone production, reducing dependence on external treatments [12]. (3) Investigation into environmental and epigenetic endocrine-disrupting factors, such as pollution, diet, and stress, and their roles in hypogonadism development [13]. (4) Immunological approaches: deeper understanding of underlying immunological mechanisms may allow for novel treatments to modulate the immune response [14].