Currently old K (Kalman syndrome) needs to be treated with long-term drug replacement therapy to maintain secondary sexual characteristics and hormonal homeostasis in the body and to improve quality of life. There are 3 main treatment options, which are carefully chosen by endocrinologists according to the patient’s age, physical condition and different needs, and the 3 treatment options can be switched between each other. Men should adhere to lifelong treatment; women should continue treatment until menopause in normal women.
Method 1: Hormone replacement therapy
Females: 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 0.5-1mg1/day) for 6-12 months; then increase the dose of estradiol (estradiol valerate 2mg1/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-progestin combination therapy is feasible (estradiol valerate 2mg1/day x 11 days, estradiol valerate 2mg + cyproterone acetate 1mg x 10 days, with withdrawal vaginal bleeding during discontinuation).
For the first 2 years of treatment, follow up at intervals of 2-3 months to observe changes in breast and uterine size. Thereafter, follow-up should be done once in 6-12 months.
Men: Testosterone replacement therapy
Testosterone replacement therapy can promote masculine expression if the patient has no need for fertility for the time being after the diagnosis of IHH. Initially, oral testosterone undecanoate pills 40mg1/day to 40mg3/day or testosterone undecanoate injection 125mg intramuscularly 1/month; after 6 months, increase to adult dose: testosterone undecanoate pills, 80mg2/day to 80mg3/day or testosterone undecanoate injection 250mg intramuscularly 1/month; this regimen gradually increases the testosterone dose to simulate the normal pubertal development process, allowing the patient to gradually The testosterone dose is gradually increased to simulate the normal process of puberty, allowing the patient to gradually develop masculine manifestations and avoiding painful erections due to too rapid elevation of testosterone.
Patients younger than 18 years old who are seen for small penis: Short-term low-dose testosterone therapy (testosterone undecanoate pills, 40 mg 1-2/day for 3 months) helps penis enlargement close to that of the same age, generally without affecting bone age and adult lifetime height.
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 a meal. Eating foods rich in fat will help the absorption of the drug.
Testosterone undecanoate injection 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.
Efficacy: masculinization can be obvious after 6 months of medication, and can approach normal adult masculinization level after 2-3 years.
Follow-up: Initial 2 years, with 2-3 months follow-up to monitor changes in secondary sexual characteristics, testicular volume, gonadotropins and testosterone. Thereafter, routine physical examinations including height, weight, testicular volume, gonadotropins, testosterone, prostate ultrasound and PSA, hemoglobin and bone mineral density may 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.
This treatment option is equivalent to replacing the work of the testes, and the average cost of treatment is $100/month.
Method 2: HCG/HMG combination therapy
Population: Old K with fertility needs.
Principle: Human chorionic gonadotropin (HCG) has the same alpha subunit and similar beta subunit as LH, which can mimic the stimulating effect of LH on testicular mesenchymal 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.
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 and dissolved in saline (or water for injection) for intramuscular injection twice a week.
Follow-up: Follow-up at intervals of 2-3 months is required to monitor blood testosterone and?HCG levels, testicular volume and semen routine; 70-85% of patients produce spermatozoa within 0.5 to 2 years of the combined medication. Genetically recombinantly engineered synthetic LH and FSH, which are more pure and can be self-administered subcutaneously by patients, are expensive and have similar efficacy to HCG+HMG combination therapy.
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 4 mL 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 spermatogenic efficacy.
Management of poor outcome: If testosterone levels are below 100ng/dl during treatment, or if there is no progressive increase in testicular volume and no detectable sperm in semen during 2 years of treatment, discontinuation of the drug or trial of pulsatile GnRH therapy may be considered.
Other: Some literature suggests that HCG alone can maintain spermatogenesis after a large amount of sperm production; when there is a large amount of sperm production, sperm freezing is feasible if the patient has no need to have children for a while; if only a small amount of sperm is produced by long-term treatment and the wife cannot have a natural pregnancy 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; after successful childbirth If no sperm is detected in the semen, epididymal or testicular sperm extraction can be attempted.
This treatment protocol is equivalent to replacing the pituitary gland and the average cost of treatment is $300/month.
Method 3: GNRH pulse pump therapy
1. GnRH pulse therapy uses the GnRH drug: Gonarelin, which is injected intravenously for 2 minutes, the blood concentration reaches its peak, and the half-life is 20 minutes, which is very suitable for simulating GnRH pulse. Other types of long-acting GnRH analogues are usually used to interfere with normal GnRH secretion in the hypothalamus, so they are not recommended for pulse therapy use.
2. Initial settings for GnRH pulse therapy
2.1 Gonarelin solution configuration and setup.
Gonarelin for injection, drawn into reservoir at a concentration of 200 μg/ml and placed in the GnRH pulse pump, connected to the infusion tube and subcutaneous infusion device.
2.2 Initial dose and frequency setting
Set pulse pump every 90 minutes 1 pulse, each time 10μg subcutaneous infusion, 24 hours a total of 16 pulses.
2.3 Trial wear period (3-5 days).
◆Patients with initial diagnosis of lHH according to the 2002 AACE diagnostic criteria
◆LH is greater than 3 times the basal value and >1mIU/ml after Gonarelin excitation test; FSH is greater than 2 times the basal value and >1mlU/ml
◆Patients who have been diagnosed with IHH, discontinue medication such as HCG, HMG, androgens or estrogen and progestin artificial cycle for at least 1 month
gnrh pulse pump efficacy:
◆After 3 days of treatment, LH and FSH levels increased rapidly with corresponding pulse fluctuations with pulse injection.
◆After 12 weeks of treatment, puberty starts to initiate (i.e. LH/FSH>0.7), the pituitary gland releases LH/FSH pulses regularly, the gonads develop, sex hormone levels rise, and sexual characteristics change.
◆After 24 weeks of treatment, male testes enlarge, penis grows and thickens, the number of morning erections and frequency of erections increase significantly, sexual desire improves significantly with semen and sperm production; women show regular menstrual flow, ovulation and luteal production.
3. GnRH pulse infusion dose adjustment.
The principle of dose adjustment is dynamic adjustment according to self sexual experience (penile morning erection, erection frequency; masturbation, seminal emission frequency, libido, sex life quality, quality of life score), physical examination (pubic hair distribution, testes, external genital development, breast development Tanner score), sex hormone examination (FSH, LH, E2, T, P, PRL) and the results of gonadal ultrasound, every 1 to 3 months Follow-up visits should be made, and those male patients treated for more than 6 months should also refer to routine semen examination. Dose adjustment must be made under the guidance of a professional physician and should not be easily changed.
4. GnRH pulse input frequency adjustment
Generally GnRH pulse frequency is fixed at 90 minutes, which can have ideal treatment effect for all male patients and more than 80% of female patients without adjustment.
However, for a small number of female IHH patients, fixed frequency GnRH pulses can only promote follicle formation (LH, FSH, E2 in the normal range of follicular phase, ultrasound suggestive of ovarian polycystic structures and endometrium <8mm) and cannot induce ovulation and menstrual flow. For such patients, if there is still no ovulatory menstrual cycle after 6 months of fixed frequency treatment, frequency GnRH pulse therapy can be considered.
5. Drug elution period before GnRH pulse therapy
(1) HCG, HMG, androgen or estrogen-progestin replacement therapy should be stopped for at least 1 month before GnRH pulse therapy.
(2) During GnRH pulse therapy, try to avoid the use of sex hormone-related drugs that interfere with the hypothalamic-pituitary-gonadal axis.
6. Termination of treatment
(1) Prompt termination of GnRH pulse therapy in female patients within 2 months of gestation is recommended based on physiological mechanisms and experience with clinical use, but evidence-based medical evidence is lacking.
(2) All patients who have successfully given birth through GnRH pulse therapy and have no desire to have any more children may terminate GnRH pulse therapy and switch to sex hormone replacement therapy for maintenance.
(3) GnRH pulse therapy should be discontinued in patients with no gonadal development after 24 months of use.
Currently limited to GNRH pulse pumps in China, this approach is suitable for most patients with a functioning pituitary gland. It is equivalent to carrying around a small auto-infuser. A more ideal and consistent treatment with the working principles of the gonadal axis, it uses a GnRH pulsatile syringe pump for subcutaneous injection, which stimulates the pituitary gland to release FSH and LH, which in turn stimulates testicular development, androgen secretion and sperm production. The advantage is that it is closest to the endocrine pattern of a normal person. The disadvantage is that there is a needle and pump hanging on the stomach all the time, and there are frequent changes of medication and materials, and the GNRH pulse pump costs $29,800 in China, and close to $1,000 per month.
Either treatment goes according to the working principle of the gonadal axis of hypothalamus → pituitary → gonads/organs.
Treatment for Kalman’s syndrome is lifelong, do not be impatient, and the outcome varies for each individual. It can be said that there are a hundred patients and a hundred results. Some patients feel something after just a few days of treatment, some need to take dozens of days, months, or even longer; some change their voice after a few shots of HCG, some take months, some grow a beard after treatment, some do not.
Countless individuals will have countless differences and countless treatment effects. There are many reasons for the differences: 1. age gap at the time of treatment, 2. drug sensitivity, 3. differences in the degree of sexual characteristics before treatment, 4. the amount and type of medication used, 5. genetic or individual physical differences, etc.
Different patients should choose the right treatment for themselves according to their different physical differences and not blindly listen to them. The best may not be the most suitable, but the most suitable is what we need most!