When Lifelong Anosmia Reveals Hypogonadism: A Case of Kallmann Syndrome with Primary Amenorrhea

Background

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by inappropriately low gonadotropin-releasing hormone (GnRH) secretion, leading to diminished luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels resulting in failure of pubertal development and activation of the reproductive axis. When associated with anosmia or hyposmia, this phenotype is classified as Kallmann syndrome (KS), which results from defects in the embryologic migration of GnRH neurons from the olfactory placode to the hypothalamus, often accompanied by olfactory bulb hypoplasia or aplasia on neuroimaging.¹

Kallmann Syndrome is considered a rare disorder and accounts for a significant proportion of isolated GnRH deficiencies. While KS is more frequently recognized in males, it also occurs in females, with an incidence rate of approximately 1 in 70,000.² Recent studies suggest that Kallmann syndrome accounts for up to 20–30% of CHH cases in females. In females, KS often presents with primary amenorrhea and incomplete secondary sexual characteristics, such as partial breast development.^1,3

Primary amenorrhea is clinically defined as the failure to initiate menses by a certain age, taking into account secular trends in pubertal timing. It requires systematic evaluation of the hypothalamic-pituitary-ovarian axis, outflow tract anatomy, and potential genetic or chromosomal anomalies. Contemporary guidelines emphasize comprehensive hormonal profiling, imaging, and cytogenetic assessment in the diagnostic workup of amenorrhea to differentiate central hypogonadism from ovarian, anatomical, or functional causes.⁴

Etiologically, Kallmann syndrome displays genetic heterogeneity, with mutations identified in multiple genes regulating GnRH neuron development, migration, and secretion. Key genes associated with KS include ANOS1, FGFR1, FGF8, PROK2, PROKR2, CHD7, SOX10, and SEMA3A, which play critical roles in the embryological development of the olfactory bulb and the hypothalamic–pituitary–gonadal axis. ANOS1 is classically associated with X-linked Kallmann syndrome.⁵ Despite the diagnostic value of neuroimaging findings (absence of olfactory structures) and biochemical profiles, many cases are diagnosed late due to the misinterpretation of hormonally induced bleeding as spontaneous menarche, particularly in females with uterine hypoplasia. This misdiagnosis can lead to confusion with functional hypothalamic amenorrhea, pituitary causes such as hypothyroidism, or Müllerian anomalies, such as Müllerian agenesis.⁴ Thus, a comprehensive evaluation, including clinical history, biochemical testing, and imaging, is essential for accurate diagnosis. This report presents a rare case of Kallmann syndrome with delayed diagnosis in an adult female patient evaluated at our hospital.

Case Illustration

A 25-year-old nulligravid woman, married for one year, was referred from the Endocrinology outpatient clinic for collaborative management of Kallmann syndrome. She reported menstrual bleeding only after hormonal medication prescribed by an obstetrician–gynecologist. At 18 years of age, she sought consultation because she had not yet experienced menarche and was given norethisterone 5 mg once daily for 5 days, which induced withdrawal bleeding. This hormonally induced bleeding was initially misinterpreted as evidence of previous menstruation, leading to a diagnosis of secondary amenorrhea. However, further history revealed that she had never experienced spontaneous menarche, supporting a diagnosis of primary amenorrhea. She reported that her current condition was accompanied by an inability to perceive any odors (anosmia). She also noted sparse pubic hair development and absence of axillary hair. She admitted experiencing thelarche at the age of 11 years old. The patient denied any galactorrhea. She denied progressive weight gain. She denied having any hot flushes. The patient had been married for one year and had not conceived. The patient reported a family history of similar symptoms in her eldest sister, including anosmia and menstrual abnormality, suggesting a possible familial pattern. However, no further clinical or diagnostic information regarding the sibling was available.

On physical examination, her vital signs and anthropometric measurements were within normal limits. Her BMI was 22.3 kg/m2 (normo-weight), with body weight 55 kg and body height 155 cm. Gynecologic examination showed no abnormality of the vulva or vagina. On bimanual examination, the uterus and adnexa were not palpable. Secondary sexual characteristics were incompletely developed, with Tanner stage M3 for breast and stage P3 for pubic hair development (Figure 1).

Figure 1 Tanner staging assessment consistent with partial pubertal development. (A) Pubis appearance (Tanner P3); (B) Breast appearance (Tanner M3).

For further evaluation of amenorrhea, the patient was referred to the Reproductive Endocrinology and Infertility clinic. Transvaginal ultrasonography demonstrated an anteflexed but hypoplastic uterus measuring 3.85×1.84 × 2.47 cm, with a thin endometrium of 1.67 mm (Figure 2A). The right ovary measured 2.12×0.93 × 1.35 cm, with an estimated ovarian volume of 1.39 cm³ (Figure 2B), while the left ovary measured 1.35×0.80 × 1.08 cm, with a calculated volume of 0.45 cm³ (Figure 2C). These findings were consistent with uterine and ovarian hypoplasia.

Figure 2 Transvaginal ultrasonography results revealed uterine and ovarian hypoplasia consistent with hypo-estrogenic status. (A) Uterine hypoplasia; (B) Small right ovary measuring 2.12×0.93x1.35 cm; (C) Small left ovary measuring 1.35×0.8x1.19 cm.

Laboratory assessment showed a low–normal follicle-stimulating hormone level of 3.34 mIU/mL, suppressed luteinizing hormone of 0.72 mIU/mL, and low estradiol of 25.94 pg/mL, supporting hypogonadotropic hypogonadism. Serum prolactin was 8.39 ng/mL, free thyroxine was 1.4 ng/dL, and thyroid-stimulating hormone was 2.6 μIU/mL, all within normal limits. Cytogenetic evaluation revealed a normal female karyotype, 46,XX, without structural chromosomal abnormality or mosaicism (Figure 3).

Figure 3 Karyotyping results revealed normal female chromosome 46,XX.

Given the coexistence of hypogonadotropic hypogonadism and anosmia, neuroimaging was performed. Brain magnetic resonance imaging demonstrated bilateral absence of the olfactory bulbs, which strongly supported the diagnosis of Kallmann syndrome (Figure 4). Because prolonged hypoestrogenism was suspected, bone mineral density was also evaluated by dual-energy X-ray absorptiometry. This showed low bone mass for age, with a lumbar spine Z-score of −2.7 SD, femoral neck Z-score of −1.8 SD, and forearm Z-score of −1.0 SD, consistent with reduced bone mass related to chronic estrogen deficiency.

Figure 4 Brain MRI with contrast revealed absence of olfactory bulbs; white arrow: the site where olfactory bulbs should have located.

Based on the history of absent spontaneous menarche, lifelong anosmia, partial pubertal development, low estradiol with suppressed gonadotropins, normal 46,XX karyotype, and bilateral absence of the olfactory bulbs on MRI, the patient was diagnosed with primary amenorrhea due to hypogonadotropic hypogonadism in the setting of Kallmann syndrome. This diagnosis was clinically robust, even without genetic testing, and was further supported by the patient’s family history of similar symptoms in her sister, suggesting a hereditary component to the disorder. She was started on combined estrogen–progestin therapy (Cyclo-Progynova^®, once daily), together with vitamin D₃ 5000 IU once daily and oral calcium supplementation once daily. The treatment goal was estrogen priming to promote uterine maturation, induce cyclic bleeding, and reduce the long-term consequences of hypoestrogenism, particularly on bone health. Fertility-oriented management was planned after adequate hormonal priming.

As part of a multidisciplinary approach, the patient was referred to the Psychiatry Department for baseline psychological evaluation. No psychiatric disorder was identified. She demonstrated good insight, realistic expectations regarding fertility, and strong family support. Mental status examination was unremarkable, with a Global Assessment of Functioning score of 81–90. Supportive psychotherapy and psychoeducation were initiated, with monthly follow-up planned for continued psychological monitoring.

Discussion

Primary amenorrhea is defined as the absence of menarche by 13 years of age in girls with no secondary sexual development, absence of menarche by 15 years of age in girls with normal growth and secondary sexual development, or by 2–3 years after thelarche (breast development).⁴ Primary amenorrhea may arise from anatomic abnormalities, gonadal dysfunction, or disorders of the hypothalamic–pituitary. Therefore, a structured diagnostic approach is essential to identify the underlying etiology and guide management.

Initial evaluation includes a detailed history focusing on the timing of thelarche and adrenarche, growth patterns, chronic illness, and medication use, followed by a comprehensive physical examination emphasizing on secondary sexual characteristics and genital anatomy. Determination of uterine presence by physical examination or pelvic imaging (eg, ultrasound) is a key to distinguish outflow tract anomalies or Müllerian agenesis from central causes of amenorrhea.^4,6

The laboratory evaluation should include serum gonadotropins (FSH and LH), estradiol, prolactin, and thyroid-stimulating hormone (TSH). Hormonal patterns help differentiation between hypogonadotropic hypogonadism (low/normal gonadotropins with low estradiol), hypergonadotropic hypogonadism (high gonadotropins with low estradiol), and other systemic causes. Karyotype analysis is indicated when gonadal dysgenesis or differences of sex development are suspected, particularly in patient with absent uterus or abnormal sexual characteristics.^4,7

The combination of low FSH, low LH, and low estradiol is consistent with hypogonadotropic hypogonadism, in accordance with the ASRM 2024 diagnostic algorithm. This biochemical profile reflects impaired hypothalamic or pituitary gonadotropin secretion and warrants further assessment of the hypothalamic–pituitary axis. Magnetic resonance imaging (MRI) of this region is therefore recommended to exclude structural lesions and identify congenital causes of gonadotropin-releasing hormone (GnRH) deficiency.⁴

The diagnosis of Kallmann syndrome in this patient was established through a comprehensive assessment of clinical history, endocrine evaluation, cytogenetic analysis, and neuroimaging. Despite experiencing hormonally induced withdrawal bleeding in late adolescence, the patient never achieved spontaneous physiological menarche, fulfilling criteria for primary amenorrhea. This distinction is clinically important, as withdrawal bleeding does not indicate normal activation of the hypothalamic–pituitary–ovarian axis and may delay recognition of central hypogonadism.^6,8

Biochemically, suppressed LH, low-normal FSH and low estradiol levels in the presence of normal prolactin and thyroid function strongly support hypothalamic hypogonadotropic hypogonadism. Neuroimaging provided decisive diagnostic confirmation by demonstrating bilateral absence of the olfactory bulbs. Olfactory bulb agenesis is a hallmark anatomical feature of Kallmann syndrome and reflects the shared embryological origin of the olfactory system and gonadotropin-releasing hormone (GnRH) neurons. During early fetal development, GnRH neurons migrate from the olfactory placode toward the hypothalamus; disruption of this process results in both anosmia and GnRH deficiency. The coexistence of congenital anosmia and olfactory bulb agenesis therefore represents a pathognomonic convergence of clinical and radiological findings.²

Kallmann syndrome is a genetically heterogeneous disorder with X-linked, autosomal dominant, autosomal recessive, and oligogenic inheritance patterns. Although molecular genetic testing was not performed, a family history of similar symptoms in a first-degree relative suggests a hereditary component, consistent with reports of incomplete penetrance and variable expressivity among Kallmann-associated gene variants. The underlying pathogenesis involves defective migration of GnRH neurons, leading to impaired pubertal activation and reproductive dysfunction.^1,9

Congenital hypogonadotropic hypogonadism (CHH) is now recognized as a phenotypic continuum rather than a uniform entity, ranging from complete absence of pubertal development to partial forms with hypothalamic–pituitary–ovarian axis activity. Genotype–phenotype studies, particularly in women, demonstrate that partial loss-of-function mutations in genes regulating GnRH signaling may permit limited estrogen production, resulting in partial secondary sexual development without spontaneous menarche.¹⁰

The present patient’s phenotype is consistent with partial CHH within the Kallmann spectrum. Although the patient fulfills biochemical criteria for WHO group I anovulation—characterized by low gonadotropins and low estradiol consistent with central hypogonadism—her Tanner stage M3 breast development and positive progesterone challenge test indicate prior estrogen-mediated tissue responsiveness.¹¹ This apparent diagnostic paradox is well explained in partial CHH, where intermittent or low-amplitude GnRH secretion permits limited ovarian estrogen production, sufficient for secondary sexual characteristic development but inadequate for sustained endometrial cycling or ovulation. Such patients may therefore demonstrate estrogen-dependent features without achieving spontaneous menarche or regular menses.¹⁰

Recent studies highlight that Kallmann Syndrome is frequently underdiagnosed because partial pubertal development or hormonally induced bleeding may mask the underlying disorder. Current guidance recommends interpreting low estradiol together with amenorrhea, low/inappropriately normal gonadotropins, and a thin endometrium as evidence of central hypogonadism, while emphasizing that progesterone challenge testing adds limited diagnostic value.⁵ Recent genetic literature further shows that Congenital Hypogonadotropic Hypogonadism is highly heterogeneous, with more than 40 implicated genes, incomplete penetrance, and oligogenic inheritance, which may explain variable presentation and familial clustering.¹² In addition, newer data on pubertal induction suggest that suboptimal uterine growth remains common in hypogonadal females and support adequate estrogen priming before progestogen introduction, consistent with the management approach used in this patient.¹³

Normal female pubertal development depends on progressive reactivation of the hypothalamic–pituitary–ovarian axis, leading to sustained estradiol exposure that supports secondary sexual characteristics and maturation of internal reproductive organs. Adequate estrogen levels are essential for uterine growth, transforming the prepubertal tubular uterus into the mature pear-shaped organ. In this case, chronic hypoestrogenism due to Kallmann syndrome resulted in reduced uterine and ovarian volumes despite advanced breast development, indicating insufficient duration or magnitude of estrogen exposure to support normal uterine maturation.¹

Beyond reproductive development, estrogen plays a critical role in skeletal, cardiovascular, metabolic, and neurocognitive health. During puberty, estradiol is essential for epiphyseal closure and attainment of peak bone mass. Estrogen deficiency shifts bone remodeling toward resorption, increasing long-term fracture risk.¹³ Estrogen also exerts cardioprotective effects through modulation of lipid metabolism, endothelial function, oxidative stress, and vascular tone, while supporting cerebral perfusion and cognitive function. Consequently, prolonged hypoestrogenism is associated with increased skeletal and cardiometabolic risk.^5,13

Estrogen additionally modulates multiple neurotransmitter systems involved in mood and cognition. Although direct evidence linking Kallmann syndrome to psychiatric morbidity is limited, data from other hypoestrogenic states suggest potential vulnerability to stress-related and affective symptoms. These considerations support inclusion of mental health assessment within comprehensive care, even in patients with preserved psychosocial functioning.¹³

Management of women with Kallmann syndrome requires a lifelong, multidisciplinary approach. Hormone replacement therapy is the cornerstone of treatment, with estrogen replacement followed by progestogen in women with an intact uterus to promote uterine maturation and prevent systemic complications of estrogen deficiency. Adequate and sustained estrogen replacement is essential, as delayed or intermittent therapy may compromise bone and cardiometabolic health.¹³ In this patient, combined estrogen–progestin therapy once daily was initiated to support uterine development and systemic estrogen replacement.

After appropriate estrogen priming, fertility treatment typically involves ovulation induction with exogenous gonadotropins. When ovulation induction is unsuccessful or unavailable, assisted reproductive technologies, including in vitro fertilization, offer effective alternatives. In regions where pulsatile GnRH therapy is not accessible, gonadotropin-based protocols and assisted reproductive technologies (ART), including in vitro fertilization (IVF), represent an effective alternative. Shiraiwa et al, who documented a successful pregnancy and live birth following vitrified–warmed embryo transfer in a woman with Kallmann syndrome, emphasizing the role of ART when conventional ovulation induction is difficult or unsuccessful.¹⁴

Long-term follow-up should include regular assessment of bone mineral density using dual-energy X-ray absorptiometry, optimization of calcium and vitamin D intake, and encouragement of weight-bearing exercise.^6,13 Cardiovascular risk assessment is also recommended, with individualized hormone replacement strategies to balance endocrine benefit and metabolic safety. Psychological well-being should be periodically evaluated, as delayed diagnosis and fertility concerns may affect quality of life.

This case highlights the clinical importance of recognizing Kallmann syndrome in adult women presenting with primary amenorrhea, anosmia, and partial pubertal development. Its significance lies in demonstrating how hormonally induced withdrawal bleeding may obscure the diagnosis and delay appropriate management. Early recognition is essential to reduce the reproductive and systemic consequences of chronic hypoestrogenism and to enable timely multidisciplinary management.

This case report is limited by the absence of genetic testing due to financial constraints, the single-case design, and the short follow-up period, which precluded assessment of long-term treatment response and fertility outcomes. Dynamic endocrine testing was also not performed at the time of reporting, as management was initially focused on correction of chronic hypoestrogenism and estrogen priming for uterine maturation rather than fertility-oriented evaluation.

Conclusion

This case highlights the diagnostic challenge of Kallmann syndrome in an adult woman with primary amenorrhea, anosmia, and partial pubertal development. A key clinical takeaway is that hormonally induced withdrawal bleeding should not be mistaken for true menarche, as this may obscure the diagnosis. Early diagnosis and management are crucial to optimize reproductive and systemic health outcomes. The holistic, multidisciplinary approach includes long-term estrogen replacement, fertility planning, and surveillance of systemic sequelae. Future studies incorporating genetic evaluation and larger female cohorts are needed to improve diagnostic accuracy and management strategies in Kallmann syndrome.