Hypogonadotropic hypogonadism (HH) is a heterogeneous group of disorders caused by abnormalities in the hypothalamus and/or pituitary gland, resulting in decreased secretion of gonadotropins and sex hormones, and consequently hypogonadism. CHH can be divided into two major groups, congenital hypogonadotropic hypogonadism (CHH) and acquired hypogonadotropic hypogonadism (AHH). CHH can be divided into Kallmann syndrome (KS) and normal olfactory CHH.
There are about 14 pathogenic genes associated with AHH, including KAL1, FGFR1, PROKR2/PROK2 and CHD7 related to GnRH neuron migration, KISSl/KISSR1, LEP/LEPR, TAC3/TACR3, PCSK1 related to GnRH secretion, and GNRHR related to GnRH function. GNRHR and other genes related to the role of GnRH. Different types of HH can be caused by the same causative gene, and different causative genes can lead to the same type of H. Although the causative genes for HH vary, so far, most treatments for HH have used hormone replacement therapy. These include testosterone induction of pubertal development, human chorionic gonadotropin (hCG)/human recombinant FSH (rhFSH), pulsed GnRH induction of spermatogenesis and other treatments. Surgical treatment is also required for abnormalities such as cryptorchidism and gynecomastia.
In this article, we will review the diagnosis and treatment of male patients with HH.
Diagnosis of HH
Most male patients with HH are diagnosed in adulthood due to abnormal initiation or lack of puberty, and very few are diagnosed in infancy. This condition occurs most often in male infants born with unilateral or bilateral cryptorchidism and micropenis. Hormone secretion measurements done before 6 months of age in infants and toddlers can clarify the diagnosis, because the first peak in the secretion of FSH and LH levels is reached in infants and toddlers from 1 to 3 months of age, and in the 6th month, the secretion of FSH and LH decreases and does not rise again until puberty. Therefore, a definitive diagnosis of gonadotropin deficiency in infants and children after 6 months of age can only be presumed by cryptorchidism or micropenis, or if the affected child has a lesion that clearly points to a syndrome, such as olfactory deficiency or mirror motor (KS).
Incomplete or still not initiated puberty in males over the age of 14 is called delayed puberty. adult male patients with HH are most often seen due to micropenis, small testicular volume and absence or underdevelopment of secondary sexual characteristics. Due to the lack of sex hormones, patients have delayed epiphyseal closure, overgrowth of long bones, “eunuch-like” signs, arm span greater than body length, delayed bone age, and reduced bone density, which may be accompanied by reduced bone mass and osteoporosis in adults. Clinical hormone tests show testosterone levels <3.5 nmol/L and decreased gonadotropin levels. Ultrasound of the scrotum shows reduced testicular volume.
After confirming the patient’s hypogonadism, thyroid, adrenal, growth hormone and prolactin levels need to be checked to determine the function of the pituitary gland in secreting other hormones. MRI of the hypothalamic-pituitary region is performed to rule out the presence of occupying and infiltrative lesions. Ultrasound of the kidney is performed to check for renal malformations and dysplasia. Ask for medical history, any family history and history of major diseases and chronic diseases.
If the patient has only symptoms associated with gonadotropin and gonadotropin deficiency, the diagnosis is CHH with simple normal olfaction. if the patient also has hyposmia or absence of olfaction, the diagnosis is KS. patients with acquired HH often present with multiple pituitary hormone deficiencies and MRI abnormalities. The functional triggers include major illness, excessive dieting, androgen abuse, long-term use of glucocorticoids, opioids or psychotropic drugs. Structural etiologies include hemorrhage, craniopharyngioma, pituitary tumors, radiation or infiltrative lesions.
Currently, genetic diagnosis is only used for research purposes, but genetic testing is required for patients with a clear family history, or with manifestations pointing to a particular syndrome.
Treatment of HH
Currently, the treatment measures for HH are mainly hormone replacement therapy, including testosterone replacement therapy, exogenous hCC and/or thFSH supplementation and pulsed GnRH for cryptorchidism and some patients with gynecomastia, which still require surgery. According to statistics, although GnRH or hCG treatment can also induce testicular descent, the efficiency rate for high undescended testes is less than 20%, whereas the success rate of testicular fixation is 95%, so testicular fixation is performed as early as possible to transfer the testes to a cooler scrotal environment to maximize the protection of the spermatogenic and developmental capacity of the testes and reduce the incidence of tumors. Studies have shown that the optimal time for surgery is around 2 years of age, and premature intervention may destroy the testicular vascular tissues. Severe gynecomastia, which is not sensitive to pharmacological treatment, also needs to be treated with the help of surgery.
The following focuses on the pharmacological treatment of patients with HH.
(A) Initiation of pubertal development
1. Testosterone therapy: Currently, testosterone replacement therapy is used as the first-line treatment for initiating pubertal development in HH patients aged 12 to 13 years.
(1) Function of testosterone therapy.
Testosterone therapy mainly induces pubertal development and the appearance of secondary sexual characteristics and does not reverse infertility in patients (see below). Studies now show that 10% of patients on non-continuous testosterone replacement therapy develop a persistent reversal of hypogonadism symptoms. Therefore, when treating patients with HH, consideration should be given to discontinuing treatment for 3 to 6 months after pubertal development is complete to assess the possibility of reversal of hypogonadism in patients.
Current research has found that replacement therapy can maintain normal sexual function by bringing testosterone concentrations to the low end of normal, but restoration of bone mineral density, muscle mass, and hemoglobin concentrations requires higher concentrations of testosterone. In general, to improve metabolic function (lipid metabolism, insulin resistance, etc.) and reduce adverse effects (red blood cell proliferation, mood swings, etc.), testosterone concentrations are maintained at 15 to 20 nmol/L in most patients.
(2) Testosterone administration.
There are various dosage forms of testosterone therapy, including intramuscular preparations, oral preparations, transdermal gels and patches, etc. Intramuscular injection preparations mainly include testosterone enanthate and testosterone cypionate, both of which are long-acting preparations with a starting dose of 50-70
mg/month. Subsequently, the dose is increased every 6 months until 100-150 mg/month, and after 3-4 years, the dose is increased to 250 mg/3 weeks. The oral dosage form is testosterone undecanoate at a starting dose of 40
Testosterone undecanoate is given at a starting dose of 40 mg, which has a short half-life and can be converted to dihydrotestosterone in the intestine, and must be taken with dinner to be well absorbed.
Transdermal gels include Testim? (Pennsylvania, USA, Malverr Auxilium
Pharmaceuticals, Inc.), Testogel? (Leverkusen, Germany, Bayer Schering
pharma, Leverkusen, Germany) and 2% testosterone strength Tostran? (Calashiels, UK, by Prostrakan). Transdermal patches are Androph? (Brentford. Glaxo
Smith Kline), 2.5
mg/d, for adult doses. Experience with transdermal gels and patches is insufficient and local skin reactions can occur, and neither has been approved for induction of pubertal development in the UK.
During testosterone induction of pubertal development, growth assessment must be performed every 3 months to adjust the dose of the drug to conform to the rhythm of pubertal development and to avoid excessive testosterone replacement and premature epiphyseal closure, which may reduce the expected height. Once the patient’s masculinization induction meets expectations, any dose of testosterone can be used, and subcutaneous implantation of 0.8 to 1.2
mg of testosterone, but this method requires minor surgery and carries the risk of extrusion, infection, local fibrosis and scar formation.
(3) Adverse effects of testosterone therapy and countermeasures.
Testosterone can be converted to dihydrotestosterone in the periphery, which is 10 times more potent than testosterone on androgen receptors. Excess dihydrotestosterone can lead to complications such as erythrocytosis, acne, seborrheic dermatitis, hair loss and prostate enlargement. It has been found that mutations in the androgen receptor gene that lead to shortened CAG repeat sequences can lead to increased sensitivity to androgens in patients, when the dosage of testosterone needs to be reduced. When the erythrocyte pressure product is >55%, it indicates that the patient has erythrocytosis and the dosage of testosterone needs to be reduced by 25%, and if the patient does not respond well to dosage adjustment, treatment must be done through regular venous bloodletting.
In patients over-treated with testosterone or gonadotropins, gynecomastia may occur, which may be caused by massive testosterone aromatization of peripheral adipose tissue, especially breast tissue. This can be reversed by adjusting the drug dosage, but in some patients with increased sensitivity of the breast tissue to estrogen, additional use of an aromatase inhibitor is required although estradiol is within the reference range, anastrozole 1
mg/d, or an estradiol antagonist, tamoxifen 20
mg/d, may reverse gynecomastia with early application, but not with long-term application. For severe gynecomastia that is not sensitive to pharmacological treatment, surgical treatment should be undertaken.
Testosterone therapy may increase prostate volume, but should not be greater than in controls with normal gonadal function at the same age, and testosterone therapy does not increase prostate-specific antigen (PSA). The correlation between testosterone replacement therapy and the incidence of prostate cancer is still meta-determined, and prostate cancer rarely occurs in young men. If a patient develops prostate or lower urinary tract symptoms and the PSA is more than 2-fold elevated, or even more than 4
μg/L, they need to be referred to a urologist for a complete workup.
Studies have shown an internal link between metabolic syndrome (MS) and hypogonadism, with an increased incidence of hypogonadism reported in MS patients, as well as a greater risk of MS and diabetes in patients with reduced testosterone levels. Compared to healthy controls, CHH patients had significantly higher waist circumference, blood pressure, fasting glucose, insulin levels, and triglycerides, and significantly lower high-density lipoprotein cholesterol (HDL-C), which were worsened by testosterone treatment, resulting in a higher incidence of MS. However, it is inconclusive whether reduced HDL-C causes atherosclerosis. Another study found that patients with acquired hypogonadism have increased arterial stiffness and that testosterone treatment improves the function and structure of the arterial vasculature, but the exact mechanism is not known. Therefore, during testosterone therapy, cardiovascular risk factors should be detected and metabolic syndrome should be prevented and treated at the same time.
2.Gonadotropin therapy.
Some investigators have suggested whether early application of gonadotropin therapy can induce testicular development and induce puberty initiation. It was found that the application of gonadotropin therapy, whose main effect in the 1st year is to promote spermatogonia maturation and increase plasma testosterone levels, has the adverse effect of reducing future spermatogenesis. Pre-treatment with hCG prior to testicular fixation can result in apoptotic changes in testicular germ cells and testicular inflammation, which are not found in patients undergoing testicular fixation alone. Therefore, the simulation of physiological gonadotropin surges in infants and children in the first 6 months is not currently advocated. However, it has also been shown that treatment of infants and children with HH with FSH and LH in the early postnatal period increases testicular volume and penile length and raises plasma inhibin B and anti-mullerian hormone levels, but it is still unknown whether future reproductive potential can be improved. Therefore, the feasibility of applying gonadotropin to induce pubertal development still needs to be evaluated, but because this is a rare disease, it poses a challenge for statistical studies with large samples.
(II) Induction of spermatogenesis
1. Gonadotropin therapy: Currently, gonadotropin therapy is mostly used to induce spermatogenesis in patients, including hCG and FSH.
(1) Function and usage of gonadotropin therapy.
hCG promotes testosterone synthesis, widens the varicocele and increases the number of spermatogonia. The initial dose is usually 1500 IU, subcutaneous injection, 2 times/week, some insensitive patients need to increase the dose to 10000
IU, 2 times/week to induce normal testosterone levels. In patients without cryptorchidism and with large pre-treatment testicular volume, hCG treatment alone can induce sperm production, probably due to the residual function of FSH secretion in this group of patients. Patients who are not sensitive to hCG treatment, or who have severe oligospermia and azoospermia, require additional FSH treatment.
The current application is rhFSH at an initial dose of 75 IU, injected subcutaneously once every other day. If the effect of spermatogenesis and testicular development is not obvious, the dose can be increased to 150 IU, injected once every other day, or even 150
IU/d. hCG+FSH treatment for 6 to 24 months resulted in an increase in testicular volume in most patients and the appearance of spermatozoa in the semen of 80% to 95% of patients (except for those with undescended testes). The traditional method of gonadotropin administration is intramuscular, but subcutaneous administration is also possible, which greatly increases patient compliance.
In a study of 75 patients treated with gonadotropins, Liu et al. from Australia found that the treatment resulted in 50%
male patients with HH were fertile. The median treatment time for the presence of sperm in the semen of the patients was 7.1 months, and the median time for their wives to conceive was 28.2 months. The median sperm concentration was 5×106 to 8×106, and the patient’s wife was treated until at least mid-conception, when the embryo is stable and less likely to abort, and the patient’s sperm can be kept for cryopreservation for future assisted reproduction, saving costs. For patients who are ready to have children again in the near future, they can be treated with hCG alone to preserve their fertility; for patients who are not ready to have children in the near future, testosterone treatment can be resumed.
(2) Influencing factors and effective indicators of gonadotropin therapy.
Factors affecting gonadotropin therapy include pretreatment testicular volume, history of cryptorchidism, gonadal maturity and history of previous androgen therapy. Pretreatment testicular volume size is an independent influence on spermopoietic treatment and time to conception. Prior androgen therapy prolongs the time to induction of spermatogenesis, which may be caused by androgen-induced peritubular fibrosis and direct inhibition of spermatogenesis.
In recent years antimullerian hormone ( anii-Mullerian
hormone, AMH) has been found that the production of AMH in the testis is closely related to androgens and FSH, and the elevation of AMH in semen in the early stage of gonadotropin treatment may predict better spermatogenesis in the later stage. Therefore, semen AMH concentration can be considered as a predictor of the effect of gonadotropin therapy in HH patients.
2.Pulsatile GnRH therapy
(1) Methods of pulsatile GnRH therapy.
Pulsatile GnRH therapy can also induce spermatogenesis in patients to solve infertility problems.GnRH works mainly through a programmable portable infusion pump. The device is mounted on the abdominal wall and pulsatile GnRH is infused subcutaneously for 2h
1 time, with a starting dose of 5 μg per pulse, which can be increased once in 4 weeks with a dose of 2
μg until plasma FSH and LH reach physiological levels. During the period of GnRH treatment, plasma testosterone levels need to be tested once in 6-8 weeks, and usually rise significantly after 3-6 months, with spermatozoa appearing in semen after 18-139 weeks.
(2) Influencing factors, efficacy and adverse effects of pulsatile GnRH therapy.
Factors affecting the effect of pulsatile GnRH treatment include testicular volume, history of cryptorchidism, inhibin B, etc., of which inhibin B 60
ng/ml was used as the node of testicular developmental capacity after GnRH treatment. A small number of patients are insensitive to GnRH treatment, mostly those carrying a mutation in the KAL1 gene, probably because the mutation disrupts the GnRH signaling pathway. There is evidence that GnRH treatment has a superior effect on testicular growth rate than gonadotropin treatment, but no significant advantage on final testicular volume, spermatogenic capacity, sperm concentration, or conception rate.
Pulsatile GnRH therapy requires permanent connection of the pump to the subcutaneous infusion system and irregular change of the injection location to prevent infection, which has some impact on the patient’s life. Also, the treatment is expensive and should be chosen between gonadotropin therapy and GnRH therapy according to the patient’s wishes and specific circumstances.
In patients with intractable oligospermia or azoospermia, who are not sensitive to gonadotropin therapy, assisted reproduction techniques can be used, mainly including artificial in vitro fertilization, artificial intrauterine fertilization and intracytoplasmic single sperm microinjection in oocytes. However, genetic counseling is required prior to this.
Summary
The diagnosis of HH is not difficult to make based on the patient’s clinical presentation, laboratory tests and imaging. The current pharmacological treatment for this group of patients mainly includes testosterone to induce pubertal development and gonadotropin treatment to induce spermatogenesis. Pulsed GnRH therapy can also induce spermatogenesis, but because it is expensive and requires minor surgery, the choice should be made on a patient-by-patient basis. When adolescent patients undergo long-term replacement therapy with testosterone, the blood testosterone concentration should be tested regularly to adjust the dosage and prevent adverse effects such as premature epiphyseal closure. Short-term discontinuation of treatment is considered after the patient has fully developed in puberty to assess the possibility of hypogonadal reversal in the patient. Also, cardiovascular risk factors need to be tested because of the association between MS and HH. In gonadotropin therapy, AMH is expected to be a predictor of its effectiveness. Patients who are not sensitive to pharmacological treatment may resort to assisted reproduction techniques.