OVERVIEW

What is idiopathic hypogonadotropic hypogonadism?

Idiopathic hypogonadotropic hypogonadism, abbreviated as IHH, is also known as isolated hypogonadotropic hypogonadism or congenital hypogonadotropic hypogonadism.

Human gonadal function operates normally under the hierarchical "command" and regulation of three "departments" in the body: the hypothalamus, pituitary gland, and gonads (testes in males, ovaries in females).

These three "departments" have a top-down hierarchical relationship, where the higher level manages the lower level, and the lower level provides feedback to the higher level, which then makes corresponding adjustments to ensure normal gonadal function. If any of these "departments" malfunctions, gonadal function may be affected.

If the highest-level hypothalamus is impaired, congenital dysfunction of gonadotropin-releasing hormone (GnRH) neurons occurs, leading to disruptions in the synthesis, secretion, or action of GnRH. This results in reduced secretion of gonadotropins by the pituitary gland, subsequently causing insufficient gonadal function. The main manifestations include failure to develop during puberty and impaired gamete (sperm in males, eggs in females) production. This condition is known as idiopathic hypogonadotropic hypogonadism.

Is idiopathic hypogonadotropic hypogonadism common?

Idiopathic hypogonadotropic hypogonadism is a rare disease. Specific incidence data in China are lacking, but international data indicate an overall incidence rate of 1–10 cases per 100,000 people. It is more common in males, with a male-to-female ratio of 5:1.

What are the types of idiopathic hypogonadotropic hypogonadism?

Idiopathic hypogonadotropic hypogonadism is classified into two major types based on whether patients have olfactory impairment:

• Those with impaired olfaction are diagnosed with Kallmann syndrome;
• Those with normal olfaction are diagnosed with normosmic idiopathic hypogonadotropic hypogonadism (nIHH).

SYMPTOMS

What are the common symptoms and manifestations of idiopathic hypogonadotropic hypogonadism?

• Failure to develop secondary sexual characteristics and impaired gamete production (sperm in males, eggs in females): In males, this manifests as a high-pitched voice, small penis, absence of pubic hair, small or undescended testes, and lack of sperm production. In females, it presents as underdeveloped breasts, immature external genitalia, and primary amenorrhea (absence of menstruation).
• Delayed bone age development: Slow growth in height, lacking the typical adolescent growth spurt. Even after the typical age of puberty, height may continue to increase slowly. The upper-to-lower body segment ratio is less than 1, arm span exceeds height, and there is an increased risk of osteoporosis.
• Olfactory dysfunction: Due to abnormal development of the olfactory bulbs and tracts, 40%–60% of patients with idiopathic hypogonadotropic hypogonadism experience reduced or complete loss of smell (anosmia), making them unable to detect odors.
• Other manifestations: Midline facial defects such as cleft lip or palate, solitary kidney, brachydactyly (short fingers/toes) or syndactyly (webbed fingers/toes), skeletal deformities or dental maldevelopment, overweight or obesity, and mirror (synkinetic) movements.

CAUSES

What are the common causes of idiopathic hypogonadotropic hypogonadism?

Idiopathic hypogonadotropic hypogonadism is a congenital genetic disorder caused by genetic issues. Over 20 gene mutations have been identified to lead to this condition. Genetic screening reveals detectable mutations in approximately one-third of patients.

Who is most commonly affected by idiopathic hypogonadotropic hypogonadism?

Idiopathic hypogonadotropic hypogonadism is more prevalent in males, with a male-to-female ratio of 5:1.

Is idiopathic hypogonadotropic hypogonadism contagious?

Idiopathic hypogonadotropic hypogonadism is not contagious.

Is idiopathic hypogonadotropic hypogonadism hereditary?

Assessing the contribution of each gene mutation to disease development is challenging. Therefore, for patients with idiopathic hypogonadotropic hypogonadism who successfully conceive after treatment, the risk of their offspring inheriting the condition cannot be accurately determined.

DIAGNOSIS

What are the physical manifestations when idiopathic hypogonadotropic hypogonadism is suspected?

• In males, when bone age exceeds 12 years (determined by X-ray) or age is ≥18 years, if secondary sexual characteristics and testicular enlargement have not appeared, serum testosterone levels are significantly reduced, and gonadotropin levels (including follicle-stimulating hormone FSH and luteinizing hormone LH) are low or "normal."
• In females, if secondary sexual characteristics and menstruation have not developed by age 14, estradiol levels are low, and gonadotropin levels (including FSH and LH) are low or "normal."

When no clear cause can be identified, this condition should be suspected.

What tests are needed when idiopathic hypogonadotropic hypogonadism is suspected?

Generally, physical examinations, blood tests, hormone assays, imaging studies, olfactory tests, and genetic testing are required.

• Physical examination: For male patients, measure height, upper/lower body ratio, arm span, weight, and BMI, assess pubic hair Tanner stage, non-erect penile length, and testicular volume (usually measured with a Prader orchidometer). Cryptorchidism or testicular volume of 1–3 mL often suggests this diagnosis. For female patients, measure height, assess breast and pubic hair Tanner stages, and evaluate vulvar development.
• Blood tests: Liver/kidney function, complete blood count, and urinalysis to rule out chronic systemic diseases or malnutrition causing delayed puberty.
• Hormone assays: Sex hormones, including FSH, LH, testosterone, estradiol, and progesterone. LH levels of 0–0.7 IU/L suggest this condition. Other hormones (growth hormone, IGF-1, prolactin, ACTH, cortisol, 24-hour urinary free cortisol, free T4, TSH) help exclude other endocrine disorders.
• Imaging studies: Pituitary MRI to rule out hypothalamic/pituitary lesions; bone density, renal ultrasound, and bone age assessment (bone age is crucial for evaluating growth and differential diagnosis).
• GnRH stimulation test: Intravenous GnRH injection with LH measured at baseline and 60 minutes. In males, LH >8 IU/L at 60 minutes rules out this condition. Alternatively, a triptorelin stimulation test: intramuscular triptorelin with LH measured at baseline and 60 minutes. In males, LH ≤4 IU/L at 60 minutes indicates inactive gonadal axis, confirming diagnosis.
• HCG stimulation test (optional): Two methods: single HCG injection with testosterone measured at baseline, 24h, 48h, and 72h; or biweekly HCG injections for 2 weeks with testosterone measured at baseline, day 4, 7, 10, and 14. Evaluates Leydig cell function.
• Olfactory testing: Inability to distinguish alcohol, vinegar, water, or shampoo suggests Kallmann syndrome. Olfactory evoked potentials and thin-slice MRI of olfactory bulbs/tracts assess olfactory impairment.
• Genetic testing: Identifying mutations aids diagnosis.

What conditions may be confused with idiopathic hypogonadotropic hypogonadism? How to differentiate them?

This condition must be distinguished from pituitary disorders, delayed puberty due to diseases or non-pathological causes.

• Pituitary disorders: Pituitary lesions can cause hypogonadism but typically involve other hormonal deficiencies. Testing prolactin, GH, cortisol, ACTH, thyroid hormones, TSH, and pituitary MRI helps differentiation.
• Constitutional delay of puberty: A temporary delay. Most boys show pubertal signs by age 14, but some may delay until 14–18 years or later. Associated with leanness or family history. GnRH/triptorelin stimulation tests aid distinction. Rare in females.
• Chronic systemic diseases affecting puberty: Nephrotic syndrome, severe hypothyroidism, cirrhosis, or inflammatory bowel disease may cause functional delay. Puberty resumes after treating the primary condition.

TREATMENT

Which department should I visit for idiopathic hypogonadotropic hypogonadism?

Endocrinology, Pediatrics, Reproductive Medicine, Andrology, Obstetrics and Gynecology.

Can idiopathic hypogonadotropic hypogonadism resolve on its own?

Idiopathic hypogonadotropic hypogonadism generally does not resolve on its own. During long-term treatment, about 3%–20% of patients may experience spontaneous recovery of hypothalamic, pituitary, and gonadal function, known as reversal.

How is idiopathic hypogonadotropic hypogonadism treated?

Treatment for idiopathic hypogonadotropic hypogonadism is divided into therapy for males and females.

Treatment for males: There are currently three main treatment options, including androgen (testosterone) replacement therapy, gonadotropin-based spermatogenesis therapy, and pulsatile gonadotropin-releasing hormone (GnRH) therapy (pump therapy).

• Androgen replacement therapy:
  • Promotes masculinization, enabling normal sexual function and ejaculation, but does not produce sperm.
  • The penis has a sensitive window period for androgen response. During childhood and adolescence, testosterone significantly stimulates penile growth, whereas post-puberty, growth nearly stops. For patients with childhood-onset cases—such as small testes (or cryptorchidism), micropenis, and anosmia—intermittent short-term low-dose androgen therapy can help penile development approach that of peers.
• Gonadotropin therapy: Stimulates the testes to produce testosterone and sperm.
• Pulsatile GnRH therapy: Promotes pituitary secretion of gonadotropins to enhance testicular development.

Pulsatile GnRH therapy is more effective than gonadotropin therapy for spermatogenesis, producing sperm faster. Over the same treatment duration, pulsatile therapy results in larger testicular volume and higher sperm density.

Treatment for females:

• For those without fertility needs: Cyclic estrogen-progestin replacement therapy promotes secondary sexual characteristics.
• For those with fertility needs: Gonadotropin-induced ovulation therapy or pulsatile GnRH therapy (pump therapy) can be used.

Can idiopathic hypogonadotropic hypogonadism be cured?

During long-term treatment, about 3%–20% of patients may experience spontaneous recovery of hypothalamic, pituitary, and gonadal function, known as reversal.

DIET & LIFESTYLE

Does idiopathic hypogonadotropic hypogonadism require follow-up examinations? How to re-examine?

Follow-up examinations are required.

For male patients, the follow-up plan is as follows:

• During testosterone replacement therapy, gradually increase the testosterone dosage to simulate normal puberty development, allowing the patient to gradually develop masculine characteristics while avoiding painful erections caused by excessively rapid testosterone elevation.

• Significant masculinization can be observed after 6 months of treatment, and near-normal adult male levels can be achieved within 2–3 years.

• Within the first 2 years of treatment, follow up every 2–3 months to monitor secondary sexual characteristics, testicular volume, gonadotropin, and testosterone levels.

• Afterward, annual follow-ups are recommended, including routine physical examinations: height, weight, testicular volume, gonadotropin, testosterone, prostate ultrasound and prostate-specific antigen, hemoglobin, and bone density. If testicular volume progressively increases, discontinue medication and monitor closely, as the condition may reverse to normal.

• For gonadotropin-based spermatogenesis therapy, follow up every 2–3 months to monitor serum testosterone, human chorionic gonadotropin levels, testicular volume, and semen analysis.

• For pulsatile gonadotropin-releasing hormone (GnRH) spermatogenesis therapy, follow up monthly during initial treatment to monitor follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and semen analysis. Adjust the dosage and frequency of gonadorelin to maintain testosterone at mid-normal levels. Once stabilized, follow up every 3 months and adjust medication dosage based on individual conditions. Sperm production may occur as early as 3 months after treatment.

For female patients undergoing estrogen-progestogen replacement therapy, the follow-up plan is as follows:

• During the first 2 years of treatment, follow up every 2–3 months to observe changes in breast and uterine size.
• Afterward, follow up every 6–12 months.
• For ovulation induction therapy: During pulsatile GnRH therapy, follow up every 2–3 months to monitor gonadotropin, estradiol, progesterone, uterine volume, ovarian volume, and follicle count. Be vigilant for risks of ovarian hyperstimulation and follicle rupture.

Does idiopathic hypogonadotropic hypogonadism affect fertility?

Untreated idiopathic hypogonadotropic hypogonadism can impair fertility. Under the guidance of a fertility specialist, female patients undergoing gonadotropin-induced ovulation therapy achieve an oocyte retrieval rate of nearly 100%. Male patients undergoing pulsatile GnRH spermatogenesis therapy (pump therapy) have a spermatogenesis success rate of approximately 90%, significantly improving fertility success rates.

PREVENTION

Can idiopathic hypogonadotropic hypogonadism be prevented?

Currently, there are no effective measures to prevent idiopathic hypogonadotropic hypogonadism.