eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility
Gonadotropin-Releasing Hormone Deficiency in Adults: Treatment & Medication
Updated: Sep 7, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
The choice of therapy depends on the patient's desire to achieve one or more of the following: secondary sex characteristics, fertility, and bone and muscle mass.
Treatment in males
In deciding when and how to provide androgen replacement in males the patient's age, the adverse effects of therapy, and the patient's desire for fertility should be considered. In the prepubertal teenager who has congenital hypogonadism, androgens stimulate penile growth, body and facial hair growth, bone and muscle development, and voice changes. In addition, androgens stimulate growth hormone production, thus contributing to the adolescent growth spurt.
Because males with androgen deficiency can experience significant social ridicule, starting androgen therapy around age 14-15 years is prudent.
Oral, injectable, transdermal, and implantable (pellets) androgen formulations currently are available for the treatment of males with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypergonadism (IHH). The oral 17 androgens should not be used due to their toxic effects on the liver and adverse effects on lipids.
The injectable long-acting testosterone esters (eg, testosterone enanthate/cypionate) are low-cost, relatively safe, and effective, with a proven 50-year record. The disadvantages include intramuscular injection and a nonphysiologic pattern of testosterone over the dosing interval that in some men can cause wide swings in libido and mood. Research currently is being conducted on longer-acting and sustained-release formulation of testosterone injectables.
Transdermal application avoids first-pass metabolism, provides a noninvasive method of replacement, and results in more physiologic serum concentration of testosterone over a daily dosing period. Transdermal patches (scrotal and nonscrotal) and a gel preparation of testosterone are currently available. The most common adverse effect with these formulations is skin reactions at the application site. The gel preparation may be preferred by some patients because it is not visibly apparent and has fewer dermal reactions. However, the gel formulation may result in cross contamination to those in close contact with the patient.
The usual starting dose of 50-75 mg of testosterone injection is used monthly with the expectation of increasing the dose by 50 mg every 4-6 months until sexual maturation has been reached. The troublesome adverse effects of acne and gynecomastia are monitored closely and the dose adjusted accordingly. Injections (200-500 IU alternate d) of human chorionic gonadotropin (hCG) can be used in the prepubertal male. Although doses should ultimately be based on clinical response and testosterone levels, a twice-weekly dosing regimen of 100-1500 IU or 200-500 IU on alternate days is typical. The advantages of hCG are the normalization of testosterone levels and stimulation of testicular growth. The cost and numerous injections have primarily resulted in reserving hCG for men attempting fertility.
In males desiring fertility, a different approach to replacement therapy is employed. Spermatogenesis can be restored with combination of hCG and human menopausal gonadotropin (hMG, follicle-stimulating hormone [FSH], and luteinizing hormone [LH]), hCG and FSH alone, or gonadotropin-releasing hormone (GnRH) injection. Occasionally, patients may respond to hCG alone. Testicular volumes greater than 3-4 mL can be used to predict those individuals who respond to hCG. Careful monitoring of testicular size is helpful in gauging the effect of treatment. Those individuals who reach testicular sizes of 12-15 mL usually produce sperm after 12 months of treatment initiation. These hCG-only responsive individuals usually represent the fertile eunuch or patients with late-onset adult IHH.
Most patients with IHH and KS require a combination of hCG and FSH to stimulate sperm production. The starting dose for hCG is 1000 IU, and FSH is 75-150 IU on alternate days with dosage adjusted based on trough testosterone level, testicular growth, sperm production, and avoidance of adverse effects. The most common adverse effect is gynecomastia, which occurs in as many as 30% of patients. This is related to increased estrogen production from several factors, such as hCG induction of testicular aromatase and increase in the peripheral aromatization of testosterone. These monitoring periods should occur every 3 months until an adequate level of replacement is documented. Pregnancy has occurred with counts as low as 2.5 X 106, but 20-40 X 106/mL produces higher pregnancy rates. The median time to induction of spermatogenesis is 6-8 months.
The pulsatile administration of gonadotropin-releasing hormone is an effective alternative to gonadotropin administration. The dose of gonadotropin-releasing hormone ranges from 25-600 ng/kg every 2 hours delivered subcutaneously using a programmable portable infusion pump. As with gonadotropins, the dose and pulse are alternated based on testicular size, testosterone levels, spermatogenesis, and adverse effects. Once the testis has reached 8 mL, regular semen analysis can be obtained. Most patients require as long as 2 years of therapy before they reach maximal gonadal size and sperm production.
Gonadotropin-releasing hormone therapy in prepubertal boys to evoke puberty may represent a more physiologic approach because the pulse of gonadotropin-releasing hormone can be altered to mimic the natural process of puberty. Again, the response time appears to be influenced by the initial testicular size; larger testes at the start of therapy result in less time on gonadotropins or gonadotropin-releasing hormone.
Determination of which therapy to use (ie, gonadotropins or gonadotropin-releasing hormone pulses) is related more to preference than science. Therapies appear to be equally effective. The time to full testicular growth and spermatogenesis may be somewhat shorter when using gonadotropin-releasing hormone, although this appears controversial. Some anecdotal evidence suggests that gonadotropin-releasing hormone therapy has proven successful in individuals refractory to gonadotropin treatments. The disadvantage of gonadotropin-releasing hormone, beyond the need to use a pump, is that it is available only at specialized centers pending approval by the Food and Drug Administration (FDA) for this indication.
Treatment in females
In females, as in males, treatment is dictated by the fertility desires of the patient. For the woman not currently desiring fertility, estrogen replacement is required to prevent osteoporosis.
The principal estrogen produced by the functioning premenopausal ovary is estradiol-17b. Daily serum measurements of estradiol in regularly menstruating women indicate that the mean estradiol levels throughout the menstrual cycle are approximately 104 pg/mL (382 pmol/L).19 Oral and parenteral preparations (ie, subcutaneous pellets and implants, transdermal patches, vaginal creams and rings) are available for standard hormone replacement therapy in normal postmenopausal women.
Oral estrogens have the disadvantage of the first hepatic passage. Parenteral administration bypasses the intestine, avoids the first pass effect of liver metabolism, and thus prevents the abnormal E2/E1 ratio observed following oral administration.20,21 Transdermally administered 17-b estradiol has been shown to be an effective regimen for preventing bone loss in normal postmenopausal women.21 The goal is to replace sex hormones in young women by trying to mimic the normal ovarian function.
All women with intact uterus should receive a cyclical progestin. The 12-day administration of medroxyprogesterone acetate (10 mg) has been shown to adequately protect the endometrium in continuous hormone replacement therapy. Alternatively, oral micronized progesterone can be used.
Optimal hormone therapy depends on whether the patient has primary or secondary amenorrhea. Young women with primary amenorrhea in whom secondary sex characteristics have failed to develop should initially be exposed to very low doses of estrogen in an attempt to mimic the gradual pubertal maturation process. A typical regimen is as follows: 0.3 mg of conjugated equine estrogens or 25-μg estradiol patch unopposed (ie, no progestogen) daily for 6 months with incremental dose increases at 6-month intervals until the required maintenance dose is achieved. Gradual dose escalation often results in optimal breast development and allows time for the young woman to adjust psychologically to her physical maturation. Cyclical progestogen therapy, given 12-14 days per month, should be instituted toward the end of the second year of treatment.
Barrier methods of contraception should also be provided in the rare event that one of these patients spontaneously ovulates, as with women with adult-onset IHH.
Women who request fertility, similar to males, are faced with a much more complicated process. Reports of women with KS achieving a spontaneous pregnancy are rare, with only about 20 described in the literature. The medical treatment strategy is to increase gonadotropin stimulation of the ovaries; 2 pathways (exogenous or endogeneous) are recognized. Exogenous stimulation of the ovaries is accomplished with various preparations of human menopausal gonadotropin composed of FSH with different concentrations of LH. Endogeneous stimulation is accomplished with pulsatile gonadotropin-releasing hormone. Intravenous pulsatile gonadotropin-releasing hormone appears to have advantages over gonadotropins because it can be pulsed to mimic the normal menstrual dynamics. When applied to other IHH conditions, the pregnancy rate, cancellation of cycles, and multiple births rate are improved when compared to gonadotropin therapy.
Reversal of idiopathic hypogonadotropic hypogonadism
Recent reports have shown possible reversal of KS after therapy with hormone replacement.22,23 As many as 10% of males with KS have resumption of endogenous androgen production. Men who receive exogenous testosterone rarely have an increase in testicular volume. However, an increase in size reflects the impact of endogenous androgen action. Therefore, assessing reversibility of the condition after a brief discontinuation of hormonal therapy in men who demonstrate an increase in testicular volume is recommended.
In one report, adult-onset IHH was postulated to be a consequence of an altered central set point for estradiol-mediated negative feedback.24 A 31-year-old man with this condition was treated with low-dose clomiphene citrate (25-50 mg/d) for 4 months with complete reversal of the condition. This method of treatment normalized the endogenous pulsatility of the gonadotropins, testosterone production, and sexual function and, thus, may result in improved fertility.
Medication
The goals of pharmacotherapy are to reduce morbidity, prevent complications, and correct the hormone deficiency.
Hormones
These agents are used for replacement therapy in hypogonadism associated with a deficiency or absence of endogenous testosterone.
Testosterone (Depo-Testosterone, Andro-LA, Delatest, Androderm, AndroGel)
Mainstay of treatment that is low-cost, safe, and effective. Dosage adjustments are made by monitoring trough levels prior to next injection. The goal is to maintain trough level in the low-normal range.
Adult
100-200 mg IM q2-3wk
AndroGel: Apply 5 g (delivers 5 mg systemically) qd to upper arms, shoulders, or abdomen; may increase dose after 14 d if serum testosterone below normal range to 7.5-10 g (ie, 7.5-10 mg systemically)
Transdermal patch:
Androderm: Apply 5–7.5 mg/d patch, rotate application sites on back, abdomen, upper arms, or thighs
Testoderm TTS: Apply 5 mg/d patch, rotate application sites on arms, back, or upper buttocks
Pediatric
50-75 mg IM qmo initial; increase by 50 mg q4-6 mo until sexual maturation occurs
Testosterone gel or patch: Not established
May increase effects of anticoagulants
Documented hypersensitivity; severe cardiac or renal disease; benign prostatic hypertrophy with obstruction; males with carcinoma of the breast or undiagnosed genital bleeding
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Anabolic effects may enhance hypoglycemia; monitor hand and wrist q6mo to determine the rate of bone maturation; monitor for weight gain, gynecomastia, breast tenderness, edema, sleep disturbance, mood swings, libido, and benign prostatic hypertrophy; check hemoglobin and hematocrit in older men for polycythemia
Gonadotropins
These agents stimulate production of gonadal steroid hormones.
Human chorionic gonadotropin (Corex, Choron)
Spermatogenesis may be restored. In children, although doses should be based ultimately on clinical response and testosterone levels, a twice-weekly dosing regimen of 100-1500 U or 200-500 U on alternate d is typical. Advantages of hCG are normalization of testosterone levels and stimulation of testicular growth. Cost and numerous injections have led hCG to be reserved for those males attempting fertility.
Adult
1000 U IM, alternate with FSH; adjust dose based on trough testosterone level, testicular growth, sperm production, and adverse effects
Pediatric
Prepubertal male: 200-500 U IM on alternate d
None reported
Documented hypersensitivity; prostatic carcinoma; precocious puberty
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in asthma, seizure disorders, renal disease, and migraine; most common adverse effect is gynecomastia related to increased estrogen production from several factors, such as hCG induction of testicular aromatase and increase in the peripheral aromatization of testosterone; monitor q3mo until adequate level is documented
Follicle-stimulating hormone (Fertinex, Follistim)
Stimulates gonadal steroid production.
Adult
75-150 U IM, alternate with hCG
Pediatric
Not established
None reported
Documented hypersensitivity; tumor of the uterus, ovary, hypothalamus, or breast; abnormal vaginal bleeding; pregnancy
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Serious respiratory distress, thromboembolic events, and atelectasis may occur
Gonadotropin-releasing hormones
The determination of which therapy to use, gonadotropins or gonadotropin-releasing hormone pulses, is related more to preference than to science. Therapies appear to be equally effective. Time to full testicular growth and spermatogenesis may be somewhat shorter when using gonadotropin-releasing hormone, although this appears controversial. Some anecdotal evidence suggests that gonadotropin-releasing hormone therapy has proven successful in individuals refractory to gonadotropin treatments.
Gonadorelin acetate (GnRH, Factrel, Lutrepulse)
Stimulates pituitary release of luteinizing hormone. Two years of therapy may be required to reach maximal gonadal size and sperm production. Response time is influenced by initial testicular size; larger initial size yields less time on therapy. Once testis has reached 8 mL regular semen, analysis can be obtained. As with gonadotropins, dose and pulse are alternated based on testicular size, testosterone levels, spermatogenesis, and adverse effects.
Therapy in prepubertal boys may represent a more physiologic approach because the pulse of GnRH may be altered to mimic the natural process of puberty. The disadvantage of treatment, other than the need to use a pump, is that it is available at specialized centers only due to pending approval by FDA for this indication.
In females, this appears to be an effective method of stimulation of the ovary.
Adult
Males: 25-600 ng/kg SC q2h using a programmable portable infusion pump
Females: 75 ng/kg SC administered as a pulse using a programmable portable infusion pump
Pediatric
Not established
Decreases effects of PO contraceptives, digoxin, phenothiazines, and dopamine antagonists; increases effects of androgens, glucocorticoids, spironolactone, and levodopa; concurrent use of ovulation stimulators
Documented hypersensitivity; patients who have ovarian cysts or causes of anovulation other than those of hypothalamic origin; any condition that may be worsened by reproductive hormones, such as a hormonally dependent tumor
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution if pregnancy is suspected; skin reactions (local and generalized), headache, nausea, and rare anaphylactic reactions may occur; multiple pregnancy is a possibility, minimize by careful attention to the recommended doses and ultrasonographic monitoring of the ovarian response to therapy
Oral contraceptives
These agents may be used as hormone replacement therapy.
Ethinyl estradiol and norethindrone (Ovcon 35, Nordette)
In young females, low-dose PO contraception generally is an excellent method of hormone replacement. Any low-dose combination pill with 35 μ g of ethinyl estradiol or less and any progestin is appropriate. Also useful because, on occasion, these women may spontaneously ovulate and become pregnant.
Adult
21-day pack: 1 tab PO qd for 21 d; start new dosing pack 7 d after last tab is taken
28-day pack: 1 tab PO qd
Pediatric
Not established
May reduce hypoprothrombinemic effects of anticoagulants; barbiturates, hydantoins, and rifampin may decrease effects; concomitant use with penicillins or tetracyclines may decrease effects; may increase levels of carbamazepine, tricyclic antidepressants, and corticosteroids
Documented hypersensitivity; thromboembolic disorders; cerebrovascular or coronary artery disease; known or suspected breast cancer; undiagnosed abnormal vaginal bleeding; women smokers >35 y; active liver disease; pregnancy
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Use of any progestin during first 4 mo of pregnancy is not recommended; caution in thromboembolism, stroke, MI, liver tumor, or hypertension; also use caution in cardiac, renal, or hepatic insufficiency; risk of cardiovascular adverse effects increases with cigarette use and in women >35 y
Conjugated equine estrogen and medroxyprogesterone (Prempro)
Hormone replacement therapy that induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics. Inhibits secretion of pituitary gonadotropins.
Adult
0.625 mg conjugated estrogen PO
2.5-5 mg medroxyprogesterone PO qd
Combination CEE and progestin daily
Pediatric
Not established
May decrease effects of aminoglutethimide; may reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P-450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
Documented hypersensitivity; known or suspected pregnancy; breast cancer, undiagnosed abnormal genital bleeding; active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy); cerebral apoplexy; liver dysfunction
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation such as abnormal or excessive uterine bleeding or mastodynia; estrogens may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia; caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders
Conjugated estrogens (Premarin)
Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics. Titrate dose depending on the hypoestrogenic symptoms
Adult
0.625 mg PO qd, depending on tissue response of patient
Pediatric
Not established
May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
Documented hypersensitivity; known or suspected pregnancy; breast cancer; undiagnosed abnormal genital bleeding; active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation such as abnormal or excessive uterine bleeding or mastodynia; estrogens may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia
Estradiol (Climara Transdermal, Estraderm Transdermal)
Restores estrogen levels to concentrations that induce negative feedback at gonadotrophic regulatory centers. Used for the purpose of hormone replacement and induction of puberty. Acts by regulating transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences or hormone-response elements, which enhances transcription of adjacent genes and, in turn, leads to the observed effects.
Continue treatment until breakthrough menstrual bleeding occurs and then initiate cyclical therapy. This can be achieved with any of a variety of PO contraceptives or the addition of medroxyprogesterone 5 mg to an estradiol regimen during the third wk of every mo with no treatment the last wk. PO contraceptive treatment is easier for patient to follow.
Adult
Patch: 0.05-0.1 mg applied once/twice weekly (application frequency dependent on brand of patch)
Pediatric
Not established
May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control
Documented hypersensitivity; thrombophlebitis, undiagnosed vaginal bleeding
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease
Progesterone (Prometrium)
Can be administered PO, vaginally, or IM. All routes of administration are equally effective. Begin treatment 2-3 d after ovulation and continue until 10th wk of pregnancy.
Adult
Vaginal suppository: 25 mg bid
Gel 8%: 1 applicator PV qd
PO micronized: 100 mg PO tid
17-hydroxyprogesterone caproate: 250 mg IM qwk
Pediatric
Not established
Aminoglutethimide may decrease effects
Documented hypersensitivity; thrombophlebitis, carcinoma of the breast, undiagnosed vaginal bleeding
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Fluid retention may occur; caution in patients with history of depression, impaired liver function, diabetes, and epilepsy; monitor for loss of vision, proptosis, diplopia, migraine, signs of embolic disorders
Medroxyprogesterone acetate (Provera)
Increases central respiratory drive and stimulates ventilation. May increase upper airway muscular tone. Progestins stimulate central respiratory drive and may be beneficial in patients with hypoventilation.
Adult
60 mg PO divided bid/tid
Pediatric
Not recommended
Aminoglutethimide may decrease effects by increasing hepatic metabolism of medroxyprogesterone
Documented hypersensitivity; cerebral apoplexy, undiagnosed vaginal bleeding, thrombophlebitis, and liver dysfunction
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders
More on Gonadotropin-Releasing Hormone Deficiency in Adults |
| Overview: Gonadotropin-Releasing Hormone Deficiency in Adults |
| Differential Diagnoses & Workup: Gonadotropin-Releasing Hormone Deficiency in Adults |
 Treatment & Medication: Gonadotropin-Releasing Hormone Deficiency in Adults |
| Follow-up: Gonadotropin-Releasing Hormone Deficiency in Adults |
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Further Reading
Keywords
gonadotropin-releasing hormone deficiency, GnRH deficiency, luteinizing hormone, LH, isolated GnRH deficiency with or without associated anosmia, Kallmann syndrome, KS, idiopathic hypogonadotropic hypergonadism, IHH, gonadotropins, fertile eunuch, micropenis, fetal testosterone, cryptorchidism, microphallus, amenorrhea, hypogonadism, sexual dysfunction, gynecomastia, decreased testosterone production, anosmia, uterine malformation, congenital heart defects, dental agenesis, short stature, mental retardation, ichthyosis, chondroplasia punctata, cleft palate, hearing loss, adrenal hypoplasia congenita
