Idiopathic hypogonadotropic hypogonadism (IHH) is a relatively common endocrine disorder. Because of the complexity of the pathogenesis, clinical manifestations and treatment, many clinicians have many doubts about the proper diagnosis and treatment of the disease. In order to standardize and improve the diagnosis and treatment of IHH, the Gonadology Group of the Endocrinology Branch of the Chinese Medical Association organized experts to discuss the topic and developed this consensus for clinical reference.
Definition
Idiopathic/Isolated Hypogonadotropic Hypogonadism (IHH), also known as congenital hypogonadotropic hypogonadism, is a condition in which the pituitary gland secretes less gonadotropin due to a congenital defect in the GnRH neurons in the hypothalamus or an impairment in the synthesis, secretion, or action of GnRH, resulting in hypogonadism. （Congenital hypogonadotropic hypogonadism (CHH). There are two clinical categories according to whether the patient has a combination of olfactory impairment: those with impaired olfaction are called Kallmann syndrome (KS), and those with normal olfaction are called normosmic idiopathic hypogonadotropic HH (nIHH).
Etiology
More than 20 gene mutations have been identified to cause IHH, such as KAL1, FGFR1, FGF8, GnRH, GNRHR, PROK2, PROKR2, TAC3, TACR3, DAX1, NELF, CHD7, SEMA3A, SOX2, FEZF1, etc. In patients with family history, detailed analysis of their inheritance patterns may suggest certain gene mutations. For example, KAL1 mutations are predominantly X-chromosome recessive, while FGFR1 and PROKR2 mutations are predominantly autosomal dominant. If patients are screened for the above genes, mutated genes can be found in about 1/3 of patients. In recent years, 1-2 new pathogenic genes for IHH have been identified every year. Although some studies suggest that patients with FGFR1 mutations may have combined skeletal malformations and abnormal dental development, patients with PROKR2 mutations are often accompanied by overweight or obesity, and patients with KAL1 and FGFR1 mutations are prone to cryptorchidism, there is not a simple correspondence between gene mutations and clinical features. In view of this, medical centers with the condition are encouraged to screen IHH patients for pathogenic genes to accumulate more clinical experience and increase the understanding of the disease.
Clinical manifestations
1. Failure to develop secondary sexual characteristics and impaired gametogenesis: males present with a child’s voice, small penis, no pubic hair growth, small testes or cryptorchidism, and no spermatogenesis; females present with mammary gland dysplasia, infantile vulva, and primary amenorrhea.
2, delayed epiphyseal closure, upper volume/lower volume <1, fingertip distance > height, susceptible to osteoporosis.
3. Olfactory impairment: due to abnormal development of olfactory bulb and olfactory bundle, about 40%-60% of IHH patients have combined loss of smell and cannot recognize odor.
4.Other manifestations: facial midline defects, such as cleft lip and palate; isolated kidney; short fingers (toes), parallel fingers (toes); skeletal malformation or dental dysplasia; overweight and obesity; mirror movement, etc.
Diagnosis
Males >12 years of age or ≥18 years of biological age without secondary sexual characteristics and testicular enlargement, low testosterone levels (≤100ng/dl) and low or “normal” gonadotropin (FSH and LH) levels. Females with no secondary sexual characteristics and no menstruation by age 14, with low estradiol levels and low or “normal” gonadotropin levels (FSH and LH). The diagnosis of the disease is made when no clear cause is found.
The diagnosis of IHH needs to take into account age, secondary sex characteristics, gonadal volume, hormone levels and bone age, etc. For men who have not yet developed puberty at the age of 14, puberty-related tests should be performed, and those who are temporarily difficult to diagnose should be followed up and observed to clarify the final diagnosis.
1. Medical history
Focus on the following clinical manifestations: birth history, presence of accelerated height growth during puberty and continued height increase after 18 years of age (suggesting delayed epiphyseal closure), presence of pubic hair growth, ability to recognize odors, presence of delayed pubertal development or family history of fertility disorders or olfactory disorders, and presence of history of cleft lip and palate surgery. Male patients should be asked about erection and seminal emission, as well as the history of cryptorchidism surgery; female patients should be asked about breast development and menstrual flow.
2. Physical examination
For male patients, height, upper and lower volume, finger spacing, weight and BMI, pubic hair Tanner staging, penis length in non-erect state and testicular volume (comparison with Prader testicular meter) should be measured; the importance of testicular volume in the diagnosis of IHH should be emphasized: cryptorchidism or volume 1-3 ml suggests the diagnosis of IHH; volume ≥ 4 ml suggests delayed pubertal development or partial IHH; for female patients, height, breast and pubic hair Tanner staging and vulvar development maturity should be measured.
3.Auxiliary examinations.
(1) General examination: liver and kidney function, blood and urine routine, to exclude chronic systemic diseases or malnutrition causing delayed puberty development.
(2) Sex hormones: FSH, LH, testosterone, estradiol, progesterone (female); emphasis on basal state LH level: LH at 0-0.7 IU/L, suggesting IHH; LH ≥ 0.7 IU/L, suggesting delayed pubertal development or partial IHH.
(3) Other related hormones: GH/IGF-1, PRL, ACTH/cortisol (8am)/24h urinary free cortisol, FT4/TSH.
(4) Imaging: MR of the saddle area to exclude various pituitary and hypothalamic lesions; bone density, ultrasound of both kidneys and bone age.
Bone age is an important measure of growth and development and is of great value for disease identification. There are several methods to determine bone age, but the G-P mapping method is commonly used to assess age based on the skeletal morphology of the palm and wrist joints, with additional X-rays of the elbow, ankle, heel and iliac wing taken when necessary, to help determine bone age. In normal males, puberty starts naturally at the age of 12 years, but in IHH patients or those with temporary delayed puberty, the bone age is usually 2-3 years behind the biological age. In patients with temporary delayed puberty, puberty will start when bone age reaches 12 years; if there is no sign of puberty at bone age >12 years or even at epiphyseal closure, and the levels of LH, FSH and testosterone are low, the diagnosis of IHH rather than temporary delayed puberty can be confirmed.
(5) Gonarelin excitation test: intravenous gonarelin 100 μg, measurement of LH levels at 0 and 60 min: in males, LH60min≥8IU/L, suggesting hypothalamic-pituitary-gonadal axis initiation or delayed pubertal development; or treprostin excitation test: intramuscular treprostin 100 μg, measurement of LH levels at 0 and 60 min. In males, LH60min≥12 IU/L suggests full activation of hypothalamic-pituitary-gonadal axis or delayed puberty development; LH60min≤4 IU/L suggests non-activation of gonadal axis, which can be diagnosed as IHH. LH60min between 4 and 12 IU/L suggests partial impairment of gonadal axis function, which needs to be followed up; in females, LH60min≥18 IU/L suggests full activation of gonadal For women, LH60min≥18 IU/L indicates complete activation of gonadal axis function; LH60min≤6 IU/L indicates that the gonadal axis is not activated, and IHH can be diagnosed; LH60min in the range of 6-18 IU/L indicates partial impairment of gonadal axis function.
(6) HCG excitation test (optional): used to evaluate the function of testicular interstitial cells (Leydig cells), there are two main methods. Single intramuscular injection of HCG 2000-5000 IU to determine blood testosterone levels at 0, 24h, 48h and 72h. Or intramuscular injection of HCG 2000IU twice a week for 2 weeks to determine D0, D4, D7, D10 and D14 testosterone levels. Testosterone ≥100ng/dl indicates the presence of testicular mesenchymal cells, and testosterone ≥300ng/dl indicates good mesenchymal cell function. The test may have false negatives and the results should be evaluated carefully and repeated if necessary or experimental gonadotropin treatment for 3 months to observe changes in testosterone levels.
(7) Olfactory test: If the odor of alcohol, white vinegar, water and shampoo cannot be identified, the diagnosis of Kalman syndrome can be proposed. Olfactory evoked potentials and thin MR scan of olfactory bulb olfactory bundle (optional) can objectively evaluate the degree of olfactory impairment and the developmental status of olfactory bulb olfactory bundle.
Differential diagnosis
1. Multiple anterior pituitary hormone secretion disorders: In addition to impaired hypothalamic-pituitary-gonadal axis function, one or more other anterior pituitary hormone secretion defects are also present. Therefore, screening for PRL, GH-IGF-1 axis, TSH-FT4 axis, and ACTH-F axis function is required. Anterior pituitary dysplasia, pituitary stalk disruption syndrome, pituitary and hypothalamic tumors, and other saddle area lesions can cause deficiencies in secretion of various hormones in the anterior pituitary.
2.Physical delay in puberty development: also known as “temporary delay in puberty development”. The majority of boys show puberty before the age of 14. In a few boys, puberty is delayed until the age of 14-18, or even later. Despite this late puberty, they have normal height, gonadal axis function, and bone density as adults. Delayed somatic pubertal development may be associated with a thin body type or a family history of delayed pubertal development. The diagnosis of somatic delayed pubertal development is suggested if the patient has LH60min ≥ 8 IU/L in the gonaraline excitation test or LH60min ≥ 12 IU/L in the treprostinil excitation test by the time the patient reaches 12 years of age at bone age. Follow-up observation or low-dose testosterone supplementation are optional treatment options. Somatic delayed puberty in females is rare.
3, the impact of nutritional status on pubertal development: excessive dieting, long-term diarrhea and other etiological causes of malnutrition can cause delayed pubertal development or hypogonadotropic hypogonadism in both sexes. Anorexia nervosa is a common cause of amenorrhea in women. Obesity can cause cryptogenic penis and reduced testosterone levels in men, which can be easily misdiagnosed as IHH. in obese patients, testosterone levels decrease with weight gain, and their gonadotropin levels and testicular volume are generally near normal. After diet control or gastrointestinal surgery to reduce body weight, testosterone levels can be significantly increased.
4, chronic systemic diseases on pubertal development: nephrotic syndrome, severe hypothyroidism, cirrhosis of the liver, inflammatory bowel disease, etc., can cause delayed pubertal development.
5, combined with various genetic diseases or syndromes with hypogonadal axis function: common are Prader-Willi syndrome, manifested as extreme obesity and IHH; DAX-1 gene mutation, manifested as congenital adrenal hypoplasia and IHH; Laurence-Moon-Biedl syndrome, manifested as extreme obesity, diabetes mellitus and IHH.
6. Partial IHH: There are individual differences in the degree of damage to the hypothalamic-pituitary-gonadal axis. Some patients may have autonomic partial secondary sex characteristics development, increased testicular volume to 4-10 ml, erections and seminal emission, and lower than normal gonadotropin and testosterone levels. The function of the gonadal axis in such patients may return to normal in the future. Meanwhile, they are treated with spermatogenic therapy with better efficacy than patients with complete IHH.
7. Childhood IHH: IHH is often not diagnosed in male children until after the age of 18. However, some children present characteristic clinical manifestations of IHH at an early age, such as lack of micro-puberty (abnormally low gonadotropin levels from 0-12 months in newborns), small testes (or cryptorchidism), small penis and olfactory deficiency. For these children, intermittent short-term small dose androgen or HCG therapy can be given to make the penis development close to that of the same age to reduce the psychological burden of the affected children and parents, while the change of bone age should be monitored.
8. Hypergonadotropic hypogonadism: Primary gonadal dysplasia or failure due to various causes, with auxiliary examinations suggesting reduced levels of sex hormones and significantly elevated levels of gonadotropins. For example, Turner’s syndrome (typical karyotype 45, XO) is characterized by various malformations such as dwarfism, multiple moles, elbow ectropion and pubertal dysplasia; Klinefelter syndrome (typical karyotype 47, XXY) is characterized by partial pubertal development, male breast development and impaired spermatogenesis.
Treatment of male IHH
There are three main treatment options available, including testosterone replacement, gonadotropin spermatogenesis therapy and pulsed GnRH spermatogenesis therapy. The regimens can be selected according to the functional status of the patient’s hypothalamic-pituitary-gonadal axis and the patient’s needs, and can be switched from one to another. Androgen replacement therapy promotes masculinization, enabling patients to accomplish normal sexual life and ejaculation but not sperm production; gonadotropin therapy promotes testosterone and sperm production in the testes; and pulsed GnRH therapy, promotes testicular development by promoting gonadotropin secretion from the pituitary gland.
1.Testosterone replacement therapy
(1) Testosterone replacement therapy can promote masculine expression if the patient has no need for fertility for the time being after the diagnosis of IHH. The initial oral testosterone undecanoate pills 40mg 1/day to 40mg 3/day, or testosterone undecanoate injection 125mg intramuscularly 1/month; after 6 months, increase to adult dose: testosterone undecanoate pills, 80mg 2/day to 80mg 3/day or testosterone undecanoate injection 250mg intramuscularly 1/month; this program gradually increases the testosterone dose to simulate the normal pubertal development process, allowing patients to gradually appear masculine This regimen gradually increases the testosterone dose to simulate the normal pubertal development process, allowing the patient to gradually develop masculinization and avoiding painful erections due to too rapid elevation of testosterone.
(2) Patients younger than 18 years old who are seen for small penis: Short-term low-dose testosterone therapy (testosterone undecanoate pills, 40mg 1-2/day for 3 months) can help penis enlargement close to that of the same age, and generally does not affect bone age or adult lifetime height.
(3) Oral testosterone undecanoate pills are absorbed in the form of celiac particles through the intestinal lymphatics, so it is advisable to take them during or immediately after meals. Eating fat-rich food will help the absorption of the drug.
(4) Testosterone undecanoate injection preparation is an oil-based preparation. After deep intramuscular injection, the testosterone undecanoate in the oil droplets is gradually absorbed into the blood, so a single injection can maintain high testosterone levels for up to one month.
(5) Efficacy: There can be obvious masculinization after 6 months of medication, and the level of normal adult masculinity can be approached after 2-3 years.
(6) Follow-up: Initially 2 years, follow up once every 2-3 months to monitor changes in secondary sexual characteristics, testicular volume, gonadotropin and testosterone. Thereafter, routine physical examination including height, weight, testicular volume, gonadotropin, testosterone, prostate ultrasound and PSA, hemoglobin and bone density can be performed once a year; if there is a progressive increase in testicular volume, the drug should be discontinued for observation and alert to the possibility of reversal of hypothalamic-pituitary-gonadal axis function to normal.
2.HCG/HMG combined spermatogenic treatment
(1) Applicable population: IHH patients with fertility needs.
(2) Principle: Human chorionic gonadotropin (HCG) and LH have the same alpha subunit and similar beta subunit, which can mimic the stimulating effect of LH on testicular interstitial cells and promote testosterone production. Postmenopausal urotropin (HMG) contains both FSH and LH components. Therefore, combined HCG+HMG intramuscular injection can promote sperm production in the testes.
(3) Dose and regimen: first intramuscular injection of HCG 2000-3000 IU twice a week for 3 months, during which the HCG dose is adjusted to try to maintain blood testosterone at 300-500 ng/dl; then add intramuscular injection of HMG 75-150 IU 2-3 times a week in combination with HCG for spermatogenic treatment. To improve compliance, HCG and HMG can be mixed in saline (or water for injection) and injected intramuscularly twice a week.
(4) Follow-up: Follow-up at intervals of 2-3 months, monitoring of blood testosterone and ? HCG levels, testicular volume and semen routine is required; 70-85% of patients produce spermatozoa within 0.5-2 years of the combined medication. Genetically recombinantly engineered synthetic LH and FSH, which are more pure, can be injected subcutaneously by patients themselves, but are expensive and have similar efficacy to HCG+HMG combination therapy.
(5) Predictors of efficacy: initial testicular volume and the magnitude of testicular volume increase during treatment are the most important predictors of spermatogenesis. An initial testicular volume greater than 4mL is a favorable factor for successful spermatogenic treatment, whereas the opposite is true for cryptorchidism (history); a history of previous androgen therapy does not affect the efficacy of spermatogenesis.
(6) Treatment of poor efficacy: if testosterone levels are below 100ng/dl during treatment, or if there is no progressive increase in testicular volume and no spermatozoa can be detected in semen during 2 years of treatment, discontinuation of the drug or trial of pulsatile GnRH therapy can be considered.
(7) Others: Some literature suggests that HCG alone can maintain spermatogenesis after a large amount of sperm production; when a large amount of sperm is produced, sperm freezing is feasible if the patient has no need for fertility for the time being; if only a small amount of sperm is produced with long-term treatment and the wife cannot get pregnant naturally for a long time, assisted reproduction techniques are needed to improve the chance of pregnancy; if sperm is not detected in the semen, epididymal or testicular puncture can be attempted to extract sperm; successful after childbirth, if the patient has no plan to have another child, he can switch to testosterone replacement therapy program.
3.Pulsed GnRH spermatogenesis treatment
(1) Applicable population: Patients with fertility need for IHH and the presence of sufficient number of functionally intact gonadotropin cells in the anterior pituitary, as well as most patients with congenital anterior pituitary hormone deficiency.
(2) Principle: Pulsed subcutaneous injection of GnRH via tiny pumps mimics physiological GnRH release from the hypothalamus and promotes gonadotropin secretion from the pituitary gland, which in turn promotes testicular development and spermatogenesis. Therefore, the presence of sufficient numbers of well-functioning gonadotropin cells in the anterior pituitary gland is a prerequisite for successful treatment.
(3) Starting dose and follow-up: GnRH (Gonarelin) 10μg/90min. after 3 days with pump, if blood LH≥1IU/L, it indicates that the initial treatment is effective. If LH is not elevated, it suggests anterior pituitary gonadotropin cell deficiency or severely impaired function and poor treatment prognosis. Thereafter, monthly follow-up visits were conducted to monitor FSH, LH, testosterone and semen routine, adjust the dose and frequency of Gonarelin, and maintain testosterone at the normal median level as much as possible, and after stabilization, follow-up visits could be conducted once every 3 months to adjust the drug dose according to the patient’s specific condition.
(4) Spermatogenic efficacy: sperm production is possible after 3 months of treatment. The sperm production rate of non-cryptorchid testis patients is 100% at 2 years. The gradual increase in testicular volume during the treatment process indicates a good prognosis. The efficacy of pulsed GnRH spermatogenesis is better than HCG/HMG treatment.
Female IHH treatment
When there is no need for fertility, combined periodic estrogen and progestin replacement therapy is given to promote the development of secondary sexual characteristics. If there is a need for fertility, gonadotropin ovulation treatment or pulsatile GnRH treatment is feasible.
1. Estrogen and progestin replacement therapy
Try to mimic the normal pubertal development process with sex hormone supplementation. Reference regimen: Start with a low dose of estrogen (estradiol valerate 0.5-1mg 1/day) for 6-12 months; then increase the dose of estradiol (estradiol valerate 2mg 1/day) for 6-12 months; if breast development and uterine size (ultrasound) are close to or at the level of adult females, then cyclic estrogen and progestin combination therapy (estradiol valerate 2mg 1/day x 11 days, estradiol valerate 2mg + cyproterone acetate 1mg × 10 days, with withdrawal vaginal bleeding during discontinuation); the first 2 years of treatment should be followed up at 2-3 monthly intervals to observe changes in breast and uterine size. Thereafter, follow-up visits should be made once every 6-12 months.
2.Ovulation promotion treatment
Pulsed GnRH treatment can induce regular menstruation and ovulation to obtain a chance of pregnancy. Gonarelin 10μg/90min; follow up at 2-3 months interval to monitor gonadotropins, estradiol, progesterone, uterine volume, ovarian volume and follicle count; alert for ovarian hyperstimulation and risk of follicular rupture.
Or, under the guidance of an assisted reproduction specialist, perform gonadotropin ovulation treatment with an egg acquisition rate of nearly 100%.
Other treatment-related considerations
(1) HCG for cryptorchidism and micropenis: In children under 2 years of age, HCG treatment can facilitate the descent of cryptorchidism into the scrotum. Many guidelines recommend that cryptorchid descent fixation surgery should be performed within 1 year of age to minimize the impact on testicular spermatogenesis. In children, short-term HCG therapy (500-1000 IU intramuscularly twice a week for 3 months) may promote penile growth by promoting androgen production in the testes. Changes in penis, blood testosterone, height and bone age should be monitored during drug administration.
(2) Autonomic return to normal hypothalamic-pituitary-gonadal axis function (reversal): About 3-20% of patients can return to normal hypothalamic-pituitary-gonadal axis function on their own during long-term treatment, called reversal. The clinical manifestations are a gradual increase in endogenous gonadotropin levels, a gradual increase in testicular volume, and autonomous production of testosterone and sperm. At the time of diagnosis, a higher LH level in the basal state or treprostin excitation test with a relatively large basal testicular volume is an important indicator of future reversal of gonadal axis function. Therefore, it is important to monitor changes in testicular volume and gonadotropin levels during the course of treatment. In patients with endogenous LH ≥ 1IU/L, the drug should be intermittently discontinued to observe whether the function of the autonomic gonadal axis is initiated, and if necessary, repeat the treprostin excitation test to evaluate the functional status of the hypothalamic-pituitary-gonadal axis.
(3) Genetic counseling: Once the diagnosis of the causative gene is clear, the risk of disease in the offspring can be roughly inferred. The diagnosis of the causative gene is not clear in most patients. Even with the same genetic mutation, gonadal axis function can vary widely. Due to the complex relationship between genotype and clinical phenotype, it is difficult to accurately assess the risk of disease in the offspring.
(4) Routine calcium and vitamin D supplementation: Bone mineral density is reviewed at 2-3 year intervals. BMD may return to normal with long-term testosterone supplementation.
(5) Psychological assessment and treatment: Long-term hypogonadism and poor development of secondary sexual characteristics can lead to low self-esteem and seriously affect the quality of life of patients. After androgen supplementation and spermatogenesis treatment, the mood will improve with the development of secondary sex characteristics and sperm production. Therefore, psychological support should be given in a timely manner during the consultation and treatment.
(6) The effect of testosterone on substance metabolism: Long-term testosterone deficiency is related to the occurrence of obesity and diabetes. Testosterone replacement therapy will improve body components, increase insulin sensitivity and reduce C-reactive protein, thus improving metabolism of blood glucose and blood lipids. Therefore, blood glucose and lipid levels should be routinely monitored during treatment, and patients should be encouraged to maintain ideal body weight.