Figure 1. Testing algorithm to establish the diagnosis of idiopathic hypogonadotropic hypogonadism
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Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Hypogonadotropic hypogonadism (HH) is diagnosed when inappropriately low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) occur in the setting of hypogonadism. Acquired HH can result from any condition that disturbs the hypothalamic-pituitary axis. Although relatively rare, idiopathic or isolated hypogonadotropic hypogonadism (IHH) is caused by complete or partial absence of gonadotropin-releasing hormone (GnRH)-induced release of FSH and LH in the setting of otherwise normal anterior pituitary anatomy and function. Acquired causes of HH are more common than congenital HH. Congenital HH can be either isolated (IHH) or associated with other phenotypic features as part of a syndrome. IHH can be divided into Kallmann syndrome (KS), the association of IHH with anosmia (the inability to smell) (~60% of all IHH), and normosmic IHH (nIHH) (~40% of all IHH).
Management. Treatment of manifestations: to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids [testosterone or human chorionic gonadotropin (hCG) injections in males; estrogen and progestin in females]; to stimulate spermatogenesis, either combined gonadotropin therapy [hCG and human menopausal gonadotropins (hMG) or recombinant FSH (rFSH)] or pulsatile GnRH therapy; to stimulate folliculogenesis, pulsatile GnRH therapy; consider in vitro fertilization if spermatogenesis is achieved but infertility persists; treatment for decreased bone mass as needed.
Genetic counseling. IHH can be caused by an inherited or de novo chromosome abnormality, a specific syndrome associated with HH, or a disease-causing mutation in a specific gene. In probands with isolated HH without a clear etiology, IHH is more frequently simplex (i.e., single occurrence in a family) (~60%) and may not have an inherited basis. However, approximately 30% of IHH is familial and can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
Hypogonadotropic hypogonadism (HH) is characterized by inappropriately low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the setting of hypogonadism.
Figure 1. Testing algorithm to establish the diagnosis of idiopathic hypogonadotropic hypogonadism
). Its commanding role in this biologic hierarchy allows GnRH to control pulsatile gonadotropin secretion, modulate gonadal steroid feedback, and ultimately determine the initiation or suppression of pubertal development and fertility across the life cycle [Hoffman & Crowley 1982, Crowley et al 1985].
The HPG axis begins its activity in late gestation, remains active throughout the first several months of infancy, and then becomes remarkably dampened during the years of the childhood "quiescence" [Waldhauser et al 1981]. At puberty, unknown biologic triggers re-ignite GnRH secretion, resulting in full sexual maturation. Therefore, the controls of the reproductive axis are in dynamic flux, turning on and turning off in response to as-yet-unknown biologic signals at various time points in the reproductive life cycle.
Perturbations of the HPG axis result in hypogonadism.
When the primary defect affects the gonads (as can occur with surgery, radiation, or infection), the lack of negative feedback from gonadal hormones results in increased gonadotropin secretion.
Hypogonadotropic hypogonadism (HH) is characterized by inappropriately low serum concentrations of LH and FSH in the setting of hypogonadism. The impaired gonadotropin response points to a central defect involving the hypothalamus or pituitary gland.
Acquired causes of HH are more common than congenital forms (i.e., forms present at birth) and can result from any condition that disturbs the hypothalamic-pituitary axis. Although relatively rare, idiopathic or isolated hypogonadotropic hypogonadism (IHH) is an important subset of congenital HH caused by complete or partial absence of GnRH-induced release of FSH and LH in the setting of otherwise normal anterior pituitary anatomy and function. IHH has played a critical role in shedding light on the complex regulation of the reproductive axis in humans.
The clinical manifestations of HH depend on the stage of development at which the deficiency in the reproductive axis occurred (infancy, adolescence, adulthood). Depending on the timing of onset, individuals with acquired or secondary HH may have reproductive defects similar to those seen in IHH, but the findings are often accompanied by several non-reproductive clinical findings and hormone abnormalities.
Infancy. The signs of gonadotropin deficiency (micropenis and cryptorchidism) may be present at birth, but the significance of these findings is often not recognized until puberty. Micropenis (stretched penile length <1.9 cm) and cryptorchidism can be a manifestation of an early impairment in the reproductive axis in boys, which is also associated with abnormally low serum concentrations of gonadotropins and testosterone in the first months of life [Grumbach 2005].
Adolescence. At puberty, individuals with congenital or early-onset HH have abnormal sexual maturation, usually with incomplete development of secondary sexual characteristics. However, the degree to which sexual maturation is affected can vary (see Fertile eunuch variant).
The impaired sexual development can result in adult males with prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth and deepening of the voice), and decreased muscle mass. Females can have little or no breast development and primary amenorrhea. Since adrenal maturation proceeds normally, the low levels of androgens produced in the adrenal glands may allow normal onset of pubic hair growth (adrenarche) in both sexes.
Because of the failure of growth plates in the bone to fuse in the absence of sex hormones, individuals with early onset of HH typically have a eunuchoid body habitus (i.e., arm span exceeds height by ≥5 cm). Although skeletal maturation is delayed, the rate of linear growth is usually normal (save for the absence of a distinct pubertal growth spurt).
Adulthood. Although the majority of individuals with IHH "present" during adolescence, some individuals have normal sexual maturation but develop hypogonadotropism well into their adult years [Nachtigall et al 1997]. Adult males with IHH with normal virilization and in some situations, proven paternity, have biochemical parameters very similar to those of males with the congenital form, including low serum concentration of testosterone, apulsatile LH secretion, and responsiveness to a regimen of physiologic doses of exogenous GnRH [Nachtigall et al 1997].
Individuals with secondary HH occurring in adulthood may have reproductive phenotypes similar to those seen in adult-onset IHH but often have additional clinical features attributable to the underlying disorder; other pituitary hormones (in addition to gonadotropins) also tend to be disrupted.
Fertile eunuch variant. The severity of HH varies among individuals; in some individuals some degree of pubertal development can occur. At one extreme of this spectrum of abnormal pubertal development is the "fertile eunuch." Although individuals with this syndrome exhibit clinical evidence of hypogonadism associated with low serum concentration of testosterone, they do have partial pubertal development with normal or near-normal testicular volumes.
Analyses of the pulsatile pattern of gonadotropins in individuals with HH have demonstrated a rather broad spectrum of abnormal developmental patterns varying from completely absent GnRH-induced LH pulses to sleep-entrained GnRH release, indistinguishable from that of early puberty [Spratt et al 1987]. This level of GnRH activity permits spermatogenesis to occur with the potential to achieve fertility with little or no treatment [Smals et al 1978].
Hypogonadotropic hypogonadism (HH) is diagnosed clinically by the following:
| I | II | III | IV | V | |
|---|---|---|---|---|---|
| Pubic hair | None | Sparse hair that is long and slightly pigmented | Darker, coarser, curly hair | Adult hair covering pubis | Laterally distributed adult-type hair |
| Male genitalia | Childhood appearance of testes, scrotum, and penis (testicular volume <4 mL) | Enlargement of testes and penis; reddish discoloration of scrotum | Continued growth of testes and elongation of penis | Continued growth of testes, widening of the penis with growth of the glans penis; scrotal darkening | Mature adult genitalia (testicular volume >15 mL) |
| Female breast development | Papillae elevated, no breast bud | Breast bud with slightly elevated papillae | Breast and areola confluent and elevated | Areola and papillae project above breast | Mature (breast and areola confluent, papillae project) |
In IHH, men typically have Tanner stage I-II genitalia, women typically have Tanner stage I breasts, and both men and women typically have Tanner stage II-III pubic hair (since pubic hair is controlled in part by adrenal androgens).
Normal adult testicular volume is 15-20 mL. Men with congenital HH often have subnormal testicular volumes (<12 mL) and may present with pre-pubertal testicular volumes (<4 mL).
If the HH occurred in adulthood after normal sexual maturation (rare for IHH but common for acquired HH), secondary sexual characteristics may be fully developed.
Low or normal serum concentration of LH and FSH in the setting of low circulating concentrations of sex steroids [total testosterone (T) <100 ng/dL; estradiol (E2) <50 pg/mL].
). Note: Idiopathic hypogonadotropic hypogonadism (IHH) is a subset of congenital HH that features complete or partial absence of GnRH-induced release of FSH and LH observed in the setting of otherwise normal anterior pituitary anatomy and function. (See Causes.)Although the clinical manifestations of hypogonadotropic hypogonadism (IHH) are very similar to primary hypogonadism, disorders causing a primary defect in gonadal function (e.g., anorchism, partial androgen resistance, infections) are typically associated with elevated serum concentrations of gonadotropins.
Within the narrower scope of HH, IHH can sometimes be difficult to distinguish from other causes of decreased gonadotropin secretion.
Infancy. Although individuals with IHH may have cryptorchidism and microphallus at birth, these are not specific for IHH. Numerous disorders can give rise to these signs, ranging from isolated findings to genetic disorders such as Prader-Willi syndrome or abnormal pituitary development. This is particularly true for cryptorchidism, the most common birth defect of the male genitalia.
Adolescence. Perhaps the most difficult distinction to make is between congenital HH and constitutional delay of puberty (CDP). Time is a critical factor in distinguishing between these conditions. In CDP, spontaneous puberty eventually occurs, whereas in IHH spontaneous sexual maturation does not occur at any time. Evidence suggests that CDP and IHH are not discrete clinical entities but rather are part of a broader phenotypic spectrum. In families with IHH, delayed puberty occurs at a much higher frequency in otherwise "normal" family members than in the general population, suggesting that CDP may represent the mildest clinical variant of the IHH phenotype [Waldstreicher et al 1996].
Although the distinction between CDP and IHH cannot be reliably made at any age, age 18 years has traditionally been used to diagnose IHH in the absence of clinical features associated with IHH (e.g., anosmia, synkinesia). However, the recent description of IHH "reversals" occurring in persons in their 20's or beyond raises the possibility that such individuals may have a severe form of CDP.
No clinically available tests can differentiate CDP from IHH. Data analyses have verified that the mean serum concentrations of LH and sex hormones after GnRH or hCG (human chorionic gonadotropin) stimulation vary significantly between individuals with CDP and individuals with IHH. Nevertheless, the clinical utility of measuring serum LH and sex hormone concentrations after stimulation with GnRH and hCG is limited by the significant variation in individual LH and sex hormone serum concentrations, resulting in considerable overlap between groups [Degros et al 2003].
A promising new test that may help distinguish between CDP and IHH is the stimulated free alpha subunit (FAS). A peak-to-basal ratio of FAS after the administration of GnRH distinguishes one group from the other with a sensitivity and specificity in the 95% range and an overlap rate of 10% [Mainieri & Elnecave 2003]. However, given the relatively small number of individuals studied and limited follow-up, prospective validation is required to determine the true diagnostic reliability.
Estimates of the overall incidence of IHH vary from approximately 1:10,000 to 1:86,000 [Seminara et al 1998]. The true prevalence of IHH is difficult to determine as no study has performed careful reproductive phenotyping in large unselected populations. Likewise, it is even more difficult to estimate the prevalence of the more heterogeneous group of disorders resulting in HH.
In the authors' cohort of 250 individuals with IHH, males predominate, with a male-to-female ratio of nearly 4:1 [Seminara et al 1998].
Approximately two-thirds of individuals with IHH have anosmia/hyposmia (Kallmann syndrome, KS) and one-third have normosmic IHH (nIHH) [Authors, unpublished observation].
). Acquired causes of HH are more common than congenital HH and can result from any condition that disturbs the hypothalamic-pituitary axis.
Acquired (secondary) causes of hypogonadotropic hypogonadism include the following:
CNS or pituitary tumors
Pituitary apoplexy
Brain/pituitary radiation
Head trauma
Functional deficiency resulting from chronic systemic illness, eating disorders, malnutrition, hypothyroidism, hyperprolactinemia, diabetes mellitus, Cushing's disease
Systemic diseases such as hemochromatosis (see HFE-Associated Hereditary Hemochromatosis), sarcoidosis, and histiocytosis
Drugs: GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy
Congenital HH can be either isolated (IHH) or associated with other phenotypic features as part of a syndrome. Although rare, congenital forms of HH, and IHH in particular, have played a critical role in shedding light on the complex regulation of the reproductive axis in humans.
Identification of specific genes causing congenital HH has been complicated by the following:
Disease rarity
Small families as a result of reproductive defect
Delayed onset of the reproductive phenotype (i.e., late adolescence)
Incomplete penetrance (i.e., clinical manifestations absent in individuals with a known genetic defect)
Variable expressivity (i.e., different clinical phenotypes among individuals who have the identical gene defect; variable expressivity can occur in both the HH phenotype and the associated clinical findings)
Similar reproductive phenotype resulting from numerous mutations in various genes (overlapping phenotypes make it difficult to pool affected individuals to determine the genetic cause)
Idiopathic hypogonadotropic hypogonadism (IHH) refers to a subset of congenital HH caused by complete or partial absence of GnRH-induced release of FSH and LH in the setting of otherwise normal anterior pituitary anatomy and function.
Figure 2. Types of idiopathic hypogonadotropic hypogonadism
):
Kallmann syndrome (KS), which is the association of IHH with anosmia (the inability to smell) and accounts for approximately 60% of all individuals with IHH; and
| Cause | % of Kallmann Syndrome | Genetic Mechanism | Additional Findings | Reference |
|---|---|---|---|---|
| Chromosomal | Deletion Xp22.3→pter | Short stature, chondrodysplasia punctata, mental retardation, steroid sulfatase deficiency, ichthyosis | Ballabio et al 1989 | |
| Autosomal dominant | 10% | FGFR1 mutation | Cleft lip/palate, dental agenesis, brachydactyly, syndactyly, corpus callosum agenesis | Dode et al 2003, Pitteloud et al 2006 |
| 5% | PROKR2 mutation | Dode et al 2006 | ||
| <5% | PROKR2 mutation | Dode et al 2006 | ||
| X-linked | 5% | KAL1 mutation/deletion | Synkinesia 1 , unilateral renal agenesis, sensorineural hearing loss, high-arched palate, cryptorchidism and/or microphallus at birth | Georgopopulos et al 1997, Oliveira et al 2001 |
| Syndromic | Unknown | CHARGE syndrome(CHD7 mutation in 60%) | Coloboma, heart defect, choanal atresia, growth retardation, ear abnormalities | Pinto et al 2005 |
| Unknown | 70%-80% |
1. Mirror movement of digits
| Cause | % of Normosmic IHH | Genetic Mechanism | Phenotype | Reference |
|---|---|---|---|---|
| Chromosomal | Unknown | Loss of paternal 15q11.2 | Prader-Willi syndrome | Prader-Willi Syndrome |
| Autosomal dominant | <5% | FGFR1 mutation | Cleft lip/palate, dental agenesis, brachydactyly | Pitteloud et al 2006, Trarbach et al 2006 |
| Unknown | PROK2 mutation | Isolated HH | Dode et al 2006 | |
| Autosomal recessive | Unknown | PROP1, HESX1, LHX3 mutation | Combined pituitary hormone deficiency 1 | Cohen & Radovick 2002 |
| Unknown | PC1 mutation | Morbid obesity, hypocortisolism, hypoinsulinemia | Jackson et al 1997 | |
| Unknown | LEP or LEPR mutation | Morbid obesity | Clement et al 1998, Strobel et al 1998 | |
| 5%-10% | GNRHR mutation | Isolated HH | de Roux et al 1997, Cerrato et al 2006 | |
| 2%-5% | GPR54 mutation | de Roux et al 2003, Seminara et al 2003, Semple et al 2005 | ||
| Unknown | BBS gene mutations 2 | Bardet-Biedl syndrome | Bardet-Biedl Syndrome | |
| Unknown | HFE mutations | HFE-associated hereditary hemochromatosis | HFE-Assoicated Hereditary Hemochromatosis | |
| X-linked | Unknown | DAX1 mutation/deletion | X-linked adrenal hypoplasia congenita | X-Linked Adrenal Hypoplasia Congenita |
| Unknown | 85%-95% |
1. See PROP-1-Related Combined Pituitary Hormone Deficiency.
2. The 12 genes associated with BBS: BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, MKKS/BBS6, BBS7, TTC8/BBS8, B1/BBS9, BBS10, TRIM32/BBS11, BBS12
Once the diagnosis of hypogonadotropic hypogonadism (HH) has been established in an individual, the following approach can be used to determine the specific cause of HH to aid in discussions of prognosis and genetic counseling.
Family history. A three-generation family history should include questions about consanguinity and findings in the proband and relatives including: pubertal development, anosmia, craniofacial abnormalities (cleft lip/palate/missing teeth), synkinesia of the digits, microphallus and cryptorchidism, morbid obesity. If other individuals with HH or these associated findings are identified in the family, the mode of inheritance may become apparent. In the majority of individuals, however, no such family history is apparent.
Past medical history is appropriate to determine whether cryptorchidism and/or microphallus were present at birth.
Physical examination to determine the degree of hypogonadism and the presence of associated signs and symptoms can direct attention to nIHH, Kallmann syndrome, or secondary causes of HH.
Laboratory and radiologic evaluation, including measurement of serum concentrations of other pituitary hormones, serum iron studies, and hypothalamic/pituitary imaging, are useful to determine if additional pituitary deficits are present and to identify causes of secondary HH.
Molecular genetic testing is clinically available for the following disorders/genes associated with:
Kallmann syndrome: deletion of Xp22.3 or KAL1 (detectable by FISH), or mutations in KAL1 or FGFR1 (detectable by sequence analysis)
Normosmic HH: FGFR1, Prader-Willi syndrome, PROP1-related combined pituitary hormone deficiency, HESX1, Bardet-Biedl syndrome, and X-linked congenital adrenal hypoplasia
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
In probands with isolated HH without a clear etiology, IHH is more frequently simplex (i.e., single occurrence in a family) (~60%) and may not have an inherited basis. However, approximately 30% of IHH cases are familial and can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
Specific issues. Genetic counseling for individuals with HH is complicated by a number of factors, including the multiple modes of inheritance, the high frequency of simplex cases (i.e., single occurrence in a family), the small number of genes that have so far been determined to cause HH, as well as the relatively low percentage of individuals in whom genetic mutations can be found.
Variable expressivity of HH-causing genetic mutations has been documented. Thus, sibs who are phenotypically normal may have a mutation that could be expressed in their offspring.
Determining the mode of inheritance. If a family history of HH is present, it may be possible to elucidate the mode of inheritance.
If it is not possible to determine the mode of inheritance, the individual with HH should be counseled that HH may have a genetic cause, and that his/her offspring may be at risk of inheriting the mutation. Unfortunately, limited knowledge of the genes involved and the absence of clinical tests to identify mutations means that in most cases of HH it is not possible to provide accurate information on the risk to the offspring or sibs of the proband.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodologies and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only and when the gene(s) in which disease-causing mutations occur has/have not been identified. See DNA Banking for a list of laboratories offering this service.
The first step in management is to determine if the hypogonadotropic hypogonadism (HH) is congenital or the result of secondary (acquired) causes that may be reversible. Conditions resulting in secondary hypogonadotropism should be corrected first before focusing on the treatment of the hypogonadism.
In addition to treating hypogonadism, potential deterioration in bone health that may have resulted from periods of low circulating sex hormones needs to be addressed. Depending on the timing of puberty, duration of hypogonadism, and other osteoporotic risk factors (glucocorticoid excess, smoking, etc.), one should consider obtaining a bone mineral density study. (See Treatment of Manifestations.)
Treatment options for HH include sex steroids, gonadotropins, and pulsatile GnRH administration. Choice of therapy is determined by the goal(s) of treatment, i.e., to induce and maintain secondary sex characteristics and/or to bring about fertility.
As the majority of individuals with congenital HH have not progressed through puberty, one of the initial challenges in treating these patients is the initiation of the process of sexual maturation. When fertility is not immediately desired, replacement with gonadal steroids is the most practical option. Initial therapy should be started at low doses and gradually increased with the development of secondary characteristics.
For males with HH
Testosterone replacement. In boys or men with prepubertal features, normal virilization can be effectively achieved with testosterone replacement.
Usual starting doses are 25-50 mg of a long-acting testosterone ester given intramuscularly every two weeks.
The doses can be gradually increased by 25-50 mg every two to three months until full virilization is achieved.
Once adult doses (~200 mg every two weeks) are reached, further adjustments are based on serum testosterone levels.
Transdermal methods of testosterone administration can also be used; they have the added benefit of offering a more favorable pharmacokinetic profile.
Therapy should be continued indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass.
Human chorionic gonadotropin (hCG) injections can also be used to normalize serum concentration of testosterone and induce development of secondary sexual characteristics. Treatment with hCG is usually initiated at 1,000 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Although treatment with hCG can also promote testicular growth, this must be weighed against the increased risk of developing gynecomastia. Ultimately, the determination of which formulation to choose is based on the preference of the affected individual.
For females with HH. Initial treatment for congenital HH should consist of unopposed estrogen to allow optimal breast development. After a period of approximately six months, when breast development has been optimized, a progestin should be added for endometrial protection.
Many formulations of estrogens and progestins are available and these can be given in either cyclical or continuous fashion. Preference of the individual plays an important role in choosing the right treatment plan, although low estrogen formulations should be considered in individuals with clotting abnormalities (see Factor V Leiden Thrombophilia and Prothrombin Thrombophilia).
For males with HH. Although androgen administration helps maintain normal sexual function, gonadotropins are usually required to realize the fertility potential in males with HH.
Gonadotropin therapy. Traditionally, the combination of the gonadotropins hCG and human menopausal gonadotropins (hMG) or recombinant FSH (rFSH) is utilized to stimulate spermatogenesis. Treatment with hCG is usually initiated at 1,000 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentration. Males with a testicular volume greater than 4 mL are likely to achieve spermatogenesis sufficient for conception with hCG alone. However, if semen analysis reveals persistent azoospermia or marked oligospermia after six to nine months of treatment, FSH is added to the regimen at doses ranging from 37.5 to 75 IU as either hMG or a recombinant formulation.
Testicular volume must be tracked, as it is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL. Sperm function in men without a history of cryptorchidism is usually normal and conception can occur even with relatively low sperm counts.
Pulsatile GnRH stimulation. An alternative method for induction of spermatogenesis is pulsatile GnRH. As the primary defect of HH is typically localized to the hypothalamus, the pituitary responds appropriately to physiologic doses of GnRH. GnRH therapy usually fails if a pituitary defect exists, making gonadotropin therapy the treatment of choice in such cases.
Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [Whitcomb & Crowley 1990]. Although gonadotropin therapy or pulsatile GnRH stimulation can induce spermatogenesis in approximately 90%-95% of men with HH, some men have a better response to pulsatile GnRH stimulation than to gonadotropin therapy. However, pulsatile GnRH therapy is not currently approved by the Food and Drug Administration for the treatment of infertility in men and thus is only available for treatment of infertility in men at specialized research centers.
For females with HH
Pulsatile GnRH stimulation is also an approved therapy for folliculogenesis in women with HH. Intravenous administration of GnRH at various frequencies throughout the menstrual cycle closely mimics normal cycle dynamics with the resulting ovulation of a single follicle [Santoro et al 1986]. This therapy offers a clear advantage over the traditional treatment with exogenous gonadotropins, which involves higher rates of both multiple gestation and ovarian hyperstimulation syndrome. For either approach, however, the rate of conception is approximately 30% per ovulatory cycle [Martin et al 1990].
Specific treatment for decreased bone mass should be considered depending on the degree of bone mineralization. (See Evaluations Following Initial Diagnosis.)
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
23 May 2007 (me) Review posted to live Web site
1 June 2006 (jcp) Original submission
