You are in: eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility Gonadotropin-Releasing Hormone Deficiency in AdultsArticle Last Updated: Sep 7, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health Vaishali Popat is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, American Medical Association, and Endocrine Society Coauthor(s): Karim Anton Calis, PharmD, MPH, FASHP, FCCP, Professor, Medical College of Virginia, Virginia Commonwealth University, Clinical Professor, University of Maryland; Clinical Specialist, Endocrinology and Women's Health, Director, Drug Information Service, Mark O Hatfield Clinical Research Center, National Institutes of Health; Ziad Rafic Hubayter, MD, MPH, Fellow, The Howard and Georgeanna Jones Division of Reproductive endocrinology and Infertility, Department of Gynecology and Obstetrics, Johns Hopkins University, National Institute of Health, National Institute of Child Health and Human Development Editors: Bruce A Meyer, MD, MBA, Vice President for Medical Affairs, Associate Dean for Health System Affairs and Director of the Faculty Practice Plan, Professor, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Antonio V Sison, MD, Program Director, Department of Obstetrics and Gynecology, Robert Wood Johnson University Hospital; Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center; Bryan D Cowan, MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center Author and Editor Disclosure Synonyms and related 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 INTRODUCTIONSection 2 of 12
  BackgroundGonadotropin-releasing hormone (GnRH) is a neurohormone central to initiation of the reproductive hormone cascade. Pulsatile secretion of gonadotropin-releasing hormone from the hypothalamus is key in establishing normal gonadal function. Failure of this release results in isolated gonadotropin-releasing hormone deficiency that can be distinguished by partial or complete lack of gonadotropin-releasing hormone–induced luteinizing hormone (LH) pulse, normalization with gonadotropin-releasing hormone replacement, and otherwise normal hypothalamic-pituitary neuroanatomy and neurophysiology. Clinicians and scientists long have been intrigued by the findings of olfactory disturbances and concomitant reproductive dysfunction. Spanish pathologist Maestre de San Juan noted in 1856 the association between the failure of testicular development and the absence of the olfactory bulbs. However, the syndrome is named Kallmann syndrome (KS) after the American geneticist Kallmann. Kallmann, Schoenfeld, and Barrera in 1944 were the first to identify a genetic basis to this disorder.1 In 1954, de Morsier connected the syndrome of hypogonadism and anosmia with the abnormal development of the anterior portion of the brain.2 Kallmann syndrome is a rare disorder that occurs in both sexes. PathophysiologyGonadotropin-releasing hormone neurons A fundamental understanding of the anatomy, biochemistry, ontogeny, and physiology of gonadotropin-releasing hormone neurons aids in understanding the pathophysiology, diagnosis, and treatment of KS and idiopathic hypogonadotropic hypogonadism (IHH). Gonadotropin-releasing hormone and gonadotropin-releasing hormone receptors The decapeptide gonadotropin-releasing hormone is derived from posttranslation processing of a tripartite 92–amino acid (AA) pre-pro-gonadotropin-releasing hormone. The first 23 AA is a signal peptide and the last 56 AA is known as gonadotropin-releasing hormone–associated protein (GAP). Gonadotropin-releasing hormone is encoded from a single gene located on the short arm of chromosome 8. Serum levels of gonadotropin-releasing hormone are difficult to obtain due to its short half-life (2-4 min) and complete confinement to the hypophyseal-portal blood supply. Due to the small structure and ease of mutation of gonadotropin-releasing hormone, chemists have created several clinically useful gonadotropin-releasing hormone analogs. Gonadotropin-releasing hormone binds with high affinity to cell surface receptors located on the pituitary gonadotrophs. These 7 transmembrane cell surface G protein; coupled receptors activate phospholipase C. This enzyme leads to the activation of several second messenger molecules, the most important being diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). In turn, DG activates protein kinase C and causes IP3-stimulated release of calcium ions from intracellular pools. The result is the synthesis and release of follicle-stimulating hormone (FSH) and LH from the pituitary gonadotrophs. The released gonadotropins stimulate the gonads to produce steroid hormones and sperm or to release oocytes. Mutated gonadotropin-releasing hormone receptors, as predicted by the biochemistry, could result in clinical manifestation of isolated gonadotropin deficiency. The control of gonadotropin-releasing hormone and its receptor are regulated by many factors; the review of this regulation is beyond the scope of this article. Ontogeny and function The migration of gonadotropin-releasing hormone neurons follows a precise path from the nose to the forebrain in humans. The olfactory placode is composed of thickened ectoderm that is lateral to the head of the developing embryo and invaginates to form simple olfactory pits on either side of the nasal septum. The lateral epithelium of the olfactory pits gives rise to olfactory nerves. The medial portion develops into the site of initial gonadotropin-releasing hormone appearance and the terminal nerve. This ganglionated cranial nerve, the exact function of which is unknown, enters the forebrain and serves as a highway for the gonadotropin-releasing hormone neuronal migration. These migrating neurons do not contain neurosecretory vesicles until they reach the area of the arcuate nucleus in the hypothalamus. For this reason, neurons that do not reach the forebrain are unable to secrete gonadotropin-releasing hormone. The gonadotropin-releasing hormone neurons have been identified in the fetal hypothalamus at 9 weeks' gestation and are connected to the portal system by 16 weeks' gestation. At 10 weeks' gestation, gonadotropins are detectable in the pituitary, and by the 12th week, they are measurable in the bloodstream. Peripheral blood levels peak during the second trimester and decrease by term as the negative feedback mechanism develops. Gonadotropin-releasing hormone is secreted during the neonatal period, resulting in pulsatile LH and FSH secretion, which decreases by age 6 months in boys and by age 1-2 years in girls until puberty. During childhood, gonadotropin-releasing hormone is still secreted in pulsatile fashion but at reduced amplitude. The hypothalamic pulse generator is likely suppressed by a mechanism that inhibits gonadotropin-releasing hormone release but not its synthesis. This theory has been demonstrated in primates because gonadotropin-releasing hormone messenger RNA (mRNA) and proteins are abundant in the hypothalamus during an equivalent developmental stage. The mechanism that awakens the pubertal onset of gonadotropin-releasing hormone secretion still is unknown. Metabolic enzymes have been implicated, as have norepinephrine, neuropeptide gamma, aspartate, gamma-aminobutyric acid, transforming growth factor-alpha, and leptin. The pubertal period is characterized by an increase in the amplitude of gonadotropin-releasing hormone–induced LH as well as a small increase in the frequency of amplitude increases. Sex steroids are secreted from the gonads in response to this nocturnal increase in gonadotropins. Gonadotropins continue to be secreted in pulsatile fashion during adulthood. Most studies in males have shown LH pulses to occur every 2 hours, while, in females, gonadotropin-releasing hormone pulse frequency changes throughout the menstrual cycle. In the early follicular phase, gonadotropin-releasing hormone pulse frequency is every 90 minutes and increases to 60 minutes by the late follicular phase. Gonadotropin-releasing hormone pulse frequency during the luteal phase varies from 4-8 hours. Studying gonadotropin-releasing hormone secretion Studying gonadotropin-releasing hormone physiology in humans has been challenging. gonadotropin-releasing hormone itself is almost entirely confined to the portal blood supply of the pituitary, and direct sampling in humans is not feasible. Samples of gonadotropin-releasing hormone in the periphery are inaccurate because of the rapid 2-minute to 4-minute half-life. Much of the information known about gonadotropin-releasing hormone has come from animal studies. Belchetz and coworkers in the 1970s demonstrated in rhesus monkeys that pulsatile gonadotropin-releasing hormone is responsible for maintaining gonadotrope function.3 The researchers were able to differentiate between episodic and continuous stimulation causing maintenance and desensitization, respectively, of the gonadotrope response. Another animal example in unscrambling the gonadotropin-releasing hormone puzzle is the use of transgenic mice in developing immortalized gonadotropin-releasing hormone cell lines. Interestingly, implantation of these cells into the hypothalamus of gonadotropin-releasing hormone–deficient mice restores their estrus cycle. This has provided an important in vitro tool for studying neuroendocrine function. Human studies have been limited to frequent sampling studies in healthy and diseased models, the use of pharmacological probes, and genetic studies. LH has long been used as a marker of gonadotropin-releasing hormone pulse activity in humans. Most recently, the glycoprotein free alpha subunit (FAS) has been used as a marker due to its correlation with LH. FAS is useful in tracking gonadotropin-releasing hormone because of its 12- to 15-minute half-life. An estimate of endogenous gonadotropin-releasing hormone can be obtained using gonadotropin-releasing hormone antagonists as probes. Administering a gonadotropin-releasing hormone antagonist induces a gonadotropin-releasing hormone receptor blockade so that the amount of gonadotropin-releasing hormone present is inversely proportional to the amount of LH inhibitor. FrequencyUnited StatesThe incidence in the United States is 1 case per 10,000 men and 1 case per 50,000 women. InternationalBy examining military records, the incidence of KS has been estimated to be between 1 case per 86,000 in Sardinia and 1 case in 10,000 in France.4 Mortality/MorbidityThese patients do not have an increased mortality rate. RaceRace is not a factor in incidence. SexIn the referral population at Massachusetts General Hospital over a 20-year period, the male-to-female ratio was 3.9 to 1.5 A spectrum of gonadotropin-releasing hormone deficiency with various secretory patterns ranging from complete lack of LH pulse to diminished amplitude similar to early puberty occurs in both men and women, contributing to the clinical heterogeneity of the disorder. This suggests that multiple genetic determinants may control the expression of gonadotropin-releasing hormone secretion. AgeThe disease comes to attention when the patient fails to begin puberty and develops secondary sexual characteristics. CLINICALSection 3 of 12
HistoryThe age of onset, whether congenital or acquired, and the severity, whether complete or partial, determines the phenotypic expression.
PhysicalMost physical findings are related to failure of sexual maturation. These patients have eunuchoidal body habitus, with arm-span greater than height by 5 cm or more. Secondary sexual characteristics are often absent. Women have little or no breast development, and men have little or no beard development. In both genders, pubic hair may be present, as adrenarche may not be affected. Gynecomastia is not a typical feature. Gonadotropin-releasing hormone (GnRH) deficiency results in decreased testosterone as well as estrogen production. Many affected individuals are unaware of their loss of olfaction, especially those with partial defects. The testing with graded dilutions of pure scents is necessary to identify the impaired olfaction. The magnitude of gonadotropin-releasing hormone deficiency appears to correlate to the severity of anosmia. In cases where KS or IHH is suspected but cryptorchidism and microphallus are absent, an MRI may reveal olfactory bulbs, although normal olfactory bulbs have been demonstrated in only 25% of males with KS. Along with the anosmia, another interesting neurological finding is that of mirror movements related to cerebellar defects. Present in as many as 85% of patients with KS, mirroring is the involuntary movements in a limb that mirror the voluntary movements of the contralateral limb. Many associated defects have been reported in patients with KS. These can be defined as sporadic and include uterine malformation, congenital heart defects, and dental agenesis. X-linked KS can be associated with another X-linked disorder known as ichthyosis (steroid sulfatase disorder). The finding of renal agenesis/hypoplasia has been noted in some individuals with X-linked KS. Colquhoun-Kerr et al (1999) described an Australian family with a high frequency of renal agenesis in the presence or absence of the KAL1 mutation, suggesting an autosomal dominant or X-linked gene, which may independently or codependently contribute to renal agenesis.6 CausesGonadotropin-releasing hormone deficiency is inherited through autosomal dominant, autosomal recessive, and X-linked transmissions. However, more than two thirds of cases are sporadic. In fact, only 30% of cases of gonadotropin-releasing hormone deficiency are due to mutations in known genes. KAL1 gene The KAL1 gene, described in 1991, is an example of an X-linked gene controlling gonadotropin-releasing hormone secretion.7 The gene is located on the short arm of the X chromosome at Xp22.3. Deletions produce a syndrome of short stature, mental retardation, ichthyosis, chondroplasia punctata, and KS. Anosmin, the protein encoded by KAL, is similar in amino acid structure to molecules involved in neural development, such as protease inhibitors, neurophysins, and neural cell adhesion molecules. Anosmin appears to be important to the migration of the gonadotropin-releasing hormone neurons to their resting place in the hypothalamus. Most of the data on the KAL gene come from studies in chickens. The timing of KAL expression in the chicken has aided in understanding the migration defects of gonadotropin-releasing hormone neurons in human KS. KAL is expressed in 2 distinctly different periods of embryonic development. KAL expression is found in limb buds, facial mesenchyme, and the neurons innervating the extrinsic eye muscles during embryonic days. By embryonic day 5, gonadotropin-releasing hormone neurons migrate along the olfactory nerve and penetrate the olfactory bulb by embryonic day 7-8. KAL expression is increased in the olfactory bulb by embryonic day 7-8. At embryonic day 9-10, KAL expression up-regulates as synapses are formed between the olfactory nerve and the mitral cell layer. Studies have demonstrated that the migration of the nerves is controlled by the olfactory epithelium. When the olfactory placode is destroyed in the chick, KAL expression continues in the olfactory bulb. This suggests that KAL expression and olfactory nerve innervation are independent of one another. In humans, KAL transcripts are not identified at the time of olfactory nerve migration, again suggesting independence between KAL expression and olfactory nerve migration. In KS, a defect in neuron interaction rather than neuron migration has been suggested. In a study of a 19-week fetus with X-linked KS, the olfactory nerves were shown to have arrested within the meninges, whereas the gonadotropin-releasing hormone neurons were arrested in the forebrain, never reaching the hypothalamus. Both groups of neurons passed through the cribriform plate but arrested prematurely. The KAL gene may play a later role, such as controlling the penetration of gonadotropin-releasing hormone neurons into the olfactory bulb. Without KAL and without functioning synaptic connections, the olfactory nerve might atrophy and degenerate, causing the gonadotropin-releasing hormone defective migration. The KAL gene also may play a role in the development of other tissues such as facial mesenchyme, fibrous and perichondral cells, blood vessels, renal glomeruli, and developing limb buds. Again, this has been studied in the chicken. In humans, defective KAL expression in the cerebellum may be linked to nystagmus and ataxia observed in some patients with KS. Fibroblast growth factor receptor 1 There are 2 KS-related loci, KAL1 and KAL2. The former encodes anosmin and has been described earlier. KAL–2 encodes the fibroblast growth factor receptor 1 (FGFR1). The KAL2 associated disorder is inherited in an autosomal dominant manner. Associated features include cleft palate, hearing loss, agenesis of the corpus callosum, and fusion of metacarpal bones. In affected individuals, the lack of smell has a variable penetrance.8 Anosmin, a product of KAL1 gene, interacts and enhance the signaling of FGFR1.9 Thus in FGFR1 heterozygous affected women, the KAL gene, by escaping X-inactivation, may rescue the FGFR1 signaling.10 This may also explain why this condition is more prevalent in males. G protein-coupled receptor 54 G protein-coupled receptor 54 (GPR54) binds to kisspeptins and its derivatives. This receptor is widely expressed throughout the brain. It has been shown that in a large consanguineous Saudi family with 6 individuals with IHH, a homozygous single nucleotide change in exon 3 of GPR54 was found in all 6 affected individuals, resulting in substitution of a serine for the normal leucine in the second intracellular loop of the receptor (L148S) (see Media file 1). This change did not occur in the homozygous state in any unaffected family members and was not identified in any controls. This 7-transmembrane domain receptor shares highest homology, about 45%, with the galanin subfamily of receptors. The amino acid sequence is highly conserved across species, with 95% homology between the rat and mouse and 82% between mouse and human (98% in the transmembrane domains).11 A GPR54-deficient mouse model resulted in a phenotype similar to that in humans The mice had normal hypothalamic gonadotropin-releasing hormone content, but developed IHH that was responsive to gonadotropin-releasing hormone therapy. This finding suggests that gonadotropin-releasing hormone neurons are present in the hypothalamus and can synthesize the peptide but that GPR54 is necessary for processing or secretion of gonadotropin-releasing hormone. The ligand for GPR54 is identified as metastatin. Kisspeptin, a 145-amino acid precursor, gives rise to a 54 amino acid product termed metastin after cleavage. Together, this ligand/receptor combination (metastin/GPR54) can advance puberty in rodents and can overcome the amenorrhea of congenital leptin and leptin receptor deficiency, and starvation. Thus, this system is clearly a major gatekeeper of the pubertal process.12 Furthermore, this kisspeptin receptor is required for sexual differentiation of the brain and behavior.13 Gonadotropin-releasing hormone receptor The gonadotropin-releasing hormone receptor is a G protein–coupled receptor, which activates phospholipase C, mobilizing intracellular calcium. Mutations in this receptor have been described in families with hypogonadotropic hypogonadism. One case reports phenotypically normal parents heterozygous for a gonadotropin-releasing hormone receptor mutation who had a son with normal puberty and normal olfaction but with 8-mL testes and an abnormal semen analysis. Their daughter had primary amenorrhea and was infertile. LH probe frequency was normal but with low amplitude pulsation. Other reports describe gonadotropin-releasing hormone receptor mutations causing hypogonadotropic hypogonadism that presents with complete gonadotropin deficiency. An example is a male patient seeking treatment for delayed puberty presenting with no secondary sexual characteristics, cryptorchid testes, low gonadotropins, and low testosterone. The patient did not respond to gonadotropin-releasing hormone, but treatment with gonadotropins corrected testicular growth and descent. DAX1 gene Adrenal hypoplasia congenita arises from X-linked or autosomal recessive syndromes and presents in infancy with primary adrenal insufficiency. Treatable with steroids, it has resulted in affected adults developing hypogonadotropic hypogonadism. A pituitary origin for one group with hypogonadotropic hypogonadism has been suggested by the failed attempts in those patients to stimulate LH and FSH with pulsatile gonadotropin-releasing hormone. A smaller group has had gonadotropin responses to gonadotropin-releasing hormone therapy, characterizing a hypothalamic-versus-pituitary defect. The DAX1 gene has been identified at Xp21 as the gene responsible for adrenal hypoplasia congenita. As with the KAL gene, growing evidence for DAX mutation suggests a wide phenotypic range. Data has suggested that DAX1 mutations impair gonadotropin production at the levels of both the pituitary and the hypothalamus. Steroidogenic factor 1 (SF-1), a nuclear hormone receptor, plays a regulatory role in adrenal development and development of the hypothalamic-pituitary-gonadal axis. Specifically, SF-1 regulates the expression of the p450 steroid hydroxylase genes in the gonads and the adrenal cortex, regulates the MIS gene, regulates the alpha subunit of the gonadotropins, and regulates the beta subunit of LH. Another suggested role for DAX1 is as a "brake" for normal male maturation while being necessary for normal adrenal and hypothalamic/pituitary development. DAX1 has been shown to block steroidogenesis in adrenal cells by transcriptional repression. Loss of function of this repressor may lead to a host of adrenal, hypothalamic, and pituitary abnormalities. Evidence suggests that most familial cases of gonadotropin-releasing hormone deficiency are controlled by autosomal inheritance. In a study of 106 patients with gonadotropin-releasing hormone deficiency at Prokineticin 2 gene Neurogenesis persists in the olfactory bulb of the adult mammalian brain due to the chemoattractant effect of prokineticin 2 (PROK2). In PROK2-deficient mice, there is a significant reduction in olfactory bulb size and impaired neuronal migration.14, 15 Mutations in this gene and in the receptor (PROKR2) gene has been associated with the development of KS and normosmic IHH.16, 17 Digenic mutations Although most cases of IHH have been attributed to several single gene defects, Pitteloud et al reported 2 families with this condition but with 2 different gene mutations.17 As a compound heterozygote, the mutated genes may have a synergistic effect that result in hypothalamic hypogonadism. This model may explain the phenotypic variability observed within and across families with single gene defects. Furthermore, Dode at al showed another case where a patient had a mutation in both KAL1 and PROKR2 genes.16 With the advanced technology available, and the identification of the human genome, scientists are constantly shedding new light on the complex genetic transmission of KS. DIFFERENTIALSSection 4 of 12
Follicle-Stimulating Hormone Abnormalities Infertility Infertility, Male Luteinizing Hormone Deficiency Menopause Ovarian Failure
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| Drug Name | Testosterone (Depo-Testosterone, Andro-LA, Delatest, Androderm, AndroGel) |
|---|---|
| Description | 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 Dose | 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 Dose | 50-75 mg IM qmo initial; increase by 50 mg q4-6 mo until sexual maturation occurs Testosterone gel or patch: Not established |
| Contraindications | Documented hypersensitivity; severe cardiac or renal disease; benign prostatic hypertrophy with obstruction; males with carcinoma of the breast or undiagnosed genital bleeding |
| Interactions | May increase effects of anticoagulants |
| 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 |
These agents stimulate production of gonadal steroid hormones.
| Drug Name | Human chorionic gonadotropin (Corex, Choron) |
|---|---|
| Description | 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 Dose | 1000 U IM, alternate with FSH; adjust dose based on trough testosterone level, testicular growth, sperm production, and adverse effects |
| Pediatric Dose | Prepubertal male: 200-500 U IM on alternate d |
| Contraindications | Documented hypersensitivity; prostatic carcinoma; precocious puberty |
| Interactions | None reported |
| 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 |
| Drug Name | Follicle-stimulating hormone (Fertinex, Follistim) |
|---|---|
| Description | Stimulates gonadal steroid production. |
| Adult Dose | 75-150 U IM, alternate with hCG |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; tumor of the uterus, ovary, hypothalamus, or breast; abnormal vaginal bleeding; pregnancy |
| Interactions | None reported |
| Pregnancy | X - Contraindicated; benefit does not outweigh risk |
| Precautions | Serious respiratory distress, thromboembolic events, and atelectasis may occur |
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.
| Drug Name | Gonadorelin acetate (GnRH, Factrel, Lutrepulse) |
|---|---|
| Description | 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 Dose | 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 Dose | Not established |
| Contraindications | 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 |
| Interactions | Decreases effects of PO contraceptives, digoxin, phenothiazines, and dopamine antagonists; increases effects of androgens, glucocorticoids, spironolactone, and levodopa; concurrent use of ovulation stimulators |
| 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 |
These agents may be used as hormone replacement therapy.
| Drug Name | Ethinyl estradiol and norethindrone (Ovcon 35, Nordette) |
|---|---|
| Description | In young females, low-dose PO contraception generally is an excellent method of hormone replacement. Any low-dose combination pill with 35 μg of ethinyl estradiol or less and any progestin is appropriate. Also useful because, on occasion, these women may spontaneously ovulate and become pregnant. |
| Adult Dose | 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 Dose | Not established |
| Contraindications | 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 |
| Interactions | 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 |
| 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 |
| Drug Name | Conjugated equine estrogen and medroxyprogesterone (Prempro) |
|---|---|
| Description | 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 Dose | 0.625 mg conjugated estrogen PO 2.5-5 mg medroxyprogesterone PO qd Combination CEE and progestin daily |
| Pediatric Dose | Not established |
| Contraindications | 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 |
| Interactions | 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 |
| 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 |
| Drug Name | Conjugated estrogens (Premarin) |
|---|---|
| Description | 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 Dose | 0.625 mg PO qd, depending on tissue response of patient |
| Pediatric Dose | Not established |
| Contraindications | 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) |
| Interactions | 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 |
| 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 |
| Drug Name | Estradiol (Climara Transdermal, Estraderm Transdermal) |
|---|---|
| Description | 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 Dose | Patch: 0.05-0.1 mg applied once/twice weekly (application frequency dependent on brand of patch) |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; thrombophlebitis, undiagnosed vaginal bleeding |
| Interactions | 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 |
| Pregnancy | X - Contraindicated; benefit does not outweigh risk |
| Precautions | Caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease |
| Drug Name | Progesterone (Prometrium) |
|---|---|
| Description | 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 Dose | 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 Dose | Not established |
| Contraindications | Documented hypersensitivity; thrombophlebitis, carcinoma of the breast, undiagnosed vaginal bleeding |
| Interactions | Aminoglutethimide may decrease effects |
| 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 |
| Drug Name | Medroxyprogesterone acetate (Provera) |
|---|---|
| Description | 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 Dose | 60 mg PO divided bid/tid |
| Pediatric Dose | Not recommended |
| Contraindications | Documented hypersensitivity; cerebral apoplexy, undiagnosed vaginal bleeding, thrombophlebitis, and liver dysfunction |
| Interactions | Aminoglutethimide may decrease effects by increasing hepatic metabolism of medroxyprogesterone |
| Pregnancy | X - Contraindicated; benefit does not outweigh risk |
| Precautions | Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders |
The care of the patient depends on the goals of treatment, such as increase in sperm production or the initiation of ovulation. If fertility is not an issue, monitor the patient for problems associated with hypogonadism. One of the primary health concerns is osteoporosis.
For excellent patient education resources, visit eMedicine's Endocrine System Center, Women's Health Center, and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Hypopituitary, Anatomy of the Endocrine System, Menopause, Amenorrhea, Birth Control Overview, and Birth Control FAQs.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors James N Anasti, MD and Michael Cackovic, MD to the development and writing of this article.
| Media file 1: Human GPR54 receptor model. Mutations identified in patients with idiopathic hypogonadotropic hypogonadism are indicated. | |
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| Media file 2: KiSS-1 protein product model. Amino acids 1-19 are predicted to form a signal peptide. Proteolytic processing is predicted to produce kisspeptin-54, corresponding to amino acids 68-121. Shown is the C-terminal amidated decapeptide sequence, wherein biologic actively resides. | |
 | View Full Size Image | Media type: Image |