Clinicians distinguish between neonatal and late-onset HH. Neonates suffering from HH generally show normal sexual differentiation, but cryptorchidism, micropenis, and reduced testicular growth may be observed in male infants. In adolescence, HH manifests in form of pubertal developmental delays. With regards to the reproductive organs, these comprise prepubertal testes and delayed penile growth as well as primary amenorrhea. Decreased libido and sexual dysfunction are common. While males may grow to eunuchoid body proportions (excessively long arms and legs resulting in a decreased upper-to-lower body ratio and a wide arm span), poor breast development is most striking in females. Furthermore, disturbances of skeletal development may be noted as an overall delayed bone age and a reduced peak bone mass [9]. A growth of pubic and underarm hair may be reduced or absent. Affected males may maintain their high-pitched voice; the physiological pubertal breaking of the voice may not occur. Of note, affected adolescents may partially show physiological development, e.g., gonadal development, body growth, or pubarche may not be disturbed while other features are consistent with HH. The clinical picture presented by those patients is very heterogeneous. Occasionally, HH is only diagnosed upon the onset of sexual dysfunction or fertility problems in adulthood [10]. Here, analyses of semen samples often reveal oligo- or azoospermia. In general, HH may be associated with mild anemia, but this condition does rarely cause any symptoms.

• Short Stature

  stature Necrosis of pituitary gland (postpartum) Panhypopituitarism Pituitary cachexia Pituitary insufficiency NOS Pituitary short stature Sheehan's syndrome Simmonds' disease male E29.1 ICD-10-CM Diagnosis Code E29.1 Testicular hypofunction 2016 2017 [icd10data.com]

  Aged 17 years, the boy was referred because of short stature (162 cm) and overweight (62.5 kg). He presented no signs of puberty, bone age of 14.5 years and insulin resistance. His sister, aged 16 years, also displayed delayed puberty. [ncbi.nlm.nih.gov]

  Causes: Miscellaneous Prader-Willi Syndrome Obesity Short Stature Mild Mental Retardation Systemic Conditions Chronic gastrointestinal conditions Chronic Kidney Disease Gaucher's Disease Cystic Fibrosis Sickle Cell Anemia Human Immunodeficiency Virus [fpnotebook.com]

  stature Kallmann syndrome : anosmia, absent breast development, uterus is present, syndactyly, cleft palate or lip Prader-Willi syndrome : muscular hypotonia, short stature, facial dysmorphia Gaucher's disease : hepatomegaly, splenomegaly, painful bone [amboss.com]

  stature (in some cases) Adults: Loss of sexual interest (libido) in men Loss of menstrual periods (amenorrhea) in women Decreased energy and interest Loss of muscle mass in men Weight gain Exams and Tests Tests that may be done include: Blood tests to [nicklauschildrens.org]

• Virilization

  The choice of a particular hormone replacement therapy protocol aimed at virilizing the patient will depend on age at diagnosis and local practices. [ncbi.nlm.nih.gov]

• Weakness

  The two patients were admitted to emergency department for deep weakness, unresponsive anemia and severe bradycardia, requiring in one case the implanting of a monocameral pace-maker for treatment of heart failure. [ncbi.nlm.nih.gov]

  The XXY condition can affect three main areas of development: Physical development : As babies, many XXY males have weak muscles and reduced strength. They may sit up, crawl, and walk later than other infants. [web.archive.org]

  Educational services Males with 47,XXY should receive a comprehensive psychoeducational evaluation to assess their areas of strengths and weaknesses. [doi.org]

• Anemia

  There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA 1c in men with diabetes. [ncbi.nlm.nih.gov]

  In general, HH may be associated with mild anemia, but this condition does rarely cause any symptoms. [symptoma.com]

  The presence of subnormal testosterone levels has been associated with obesity, mild anemia, high CRP, low bone mineral density, and increased symptoms of hypogonadism. [endocrineweb.com]

  Causes: Miscellaneous Prader-Willi Syndrome Obesity Short Stature Mild Mental Retardation Systemic Conditions Chronic gastrointestinal conditions Chronic Kidney Disease Gaucher's Disease Cystic Fibrosis Sickle Cell Anemia Human Immunodeficiency Virus [fpnotebook.com]

• Weight Gain

  The second aim of our study was to evaluate the effect of the anti-obesity drug sibutramine in this patient who failed to respond to an intensive lifestyle intervention and exhibited continuous weight gain. [ncbi.nlm.nih.gov]

  gain or weight loss) Chronic medical diseases, including chronic inflammation or infections Kallmann syndrome is an inherited form of HH. [nicklauschildrens.org]

  gain or weight loss) Long-term (chronic) medical diseases, including chronic inflammation or infections Drug use, such as heroin or use or abuse of prescription opiate medicines Certain medical conditions, such as iron overload Kallmann syndrome is an [medlineplus.gov]

  The known side effects include gynecomastia, weight gain, visual problems, and acne. [endocrinologyadvisor.com]

• Anosmia

  Hypogonadism with anosmia Hypogonadism, anosmia Hypogonadotropic hypogonadism Hypogonadotropic hypogonadism due to follicle-stimulating hormone deficiency Hypogonadotropic hypogonadism due to isolated gonadotropin deficiency Hypogonadotropic hypogonadism [icd9data.com]

  To address this issue, we studied 2 families, one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH, in which a single-gene defect had been identified: a heterozygous FGF receptor 1 (FGFR1) mutation in pedigree 1 and a compound heterozygous [ncbi.nlm.nih.gov]

• Arthritis

  Autoimmune diseases - eg, systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. Germ cell tumours. [patient.info]

  […] treated. [1] Some people have a slightly increased risk of developing breast cancer, a rare extragonadal germ cell tumor, lung disease, varicose veins and osteoporosis as well as some autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis [rarediseases.info.nih.gov]

  […] syndrome also have an increased risk of developing involuntary trembling (tremors), breast cancer (if gynecomastia develops), thinning and weakening of the bones (osteoporosis), and autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis [ghr.nlm.nih.gov]

• Long Legs

  They tend to have tall stature and long legs and may have difficulties with speech and language development. [icd9data.com]

  Symptoms may include any of the following: Abnormal body proportions (long legs, short trunk, shoulder equal to hip size) Abnormally large breasts ( gynecomastia ) Infertility Sexual problems Less than normal amount of pubic, armpit, and facial hair Small [medlineplus.gov]

  Tall and slender, with long legs, narrow shoulders and wide hips. Gynaecomastia or history of gynaecomastia during puberty; decreased libido; history of undescended testes. [patient.info]

• Short Trunk

  Symptoms may include any of the following: Abnormal body proportions (long legs, short trunk, shoulder equal to hip size) Abnormally large breasts ( gynecomastia ) Infertility Sexual problems Less than normal amount of pubic, armpit, and facial hair Small [medlineplus.gov]

  trunk, shoulder equal to hip size) Learning disablity Speech delay Crypthochirdism Opening (meatus) of the urethra (the tube that carries urine and sperm through the penis to the outside) on the underside of the penis (hypospadias) instead of the tip [rarediseases.info.nih.gov]

• Large Breast

  Symptoms may include any of the following: Abnormal body proportions (long legs, short trunk, shoulder equal to hip size) Abnormally large breasts ( gynecomastia ) Infertility Sexual problems Less than normal amount of pubic, armpit, and facial hair Small [medlineplus.gov]

• Dyslexia

  The Orton Dyslexia Society Chester Building, Suite 382 8600 La Salle Road Baltimore, MD 21286 (410) 296-0232 Provides information on dyslexia. Has local chapters throughout the country [web.archive.org]

  It is interesting to note that both dyslexia and left-handedness have significant genetic components (Annett, 1985). [dx.doi.org]

  The risk of dyslexia and attention-deficient/hyperactivity disorder may also be higher. In addition, psychological problems such as depression are linked to most sexual disorders. [uspharmacist.com]

  Bender BAPuck MHSalbenblatt JARobinson A Dyslexia in 47,XXY boys identified at birth. Behav Genet. 1986;16343- 354 Google Scholar Crossref 51. Pasqualimi RQVidal GBur GE Psychopathology of Klinefelter's syndrome: review of thirty-one cases. [doi.org]

• Loss of Libido

  This leads to loss of libido, impotence and infertility. In these cases, treatment with gonadotropin-releasing hormone can reverse all the features of the disorder. [medical-dictionary.thefreedictionary.com]

  If untreated, this impairment can lead to school failure and loss of confidence. Clinical features The classic clinical description includes: [ 1 ] Infertility; small firm testes; decreased facial and pubic hair; loss of libido; impotence. [patient.info]

  Does the patient feel their libido is normal or has this changed? Absent libido occurs with primary hypogonadism. New onset loss of libido may be associated with hypogonadism though may be multifactorial. [endobible.com]

  At presentation, patients complained of sexual dysfunction and/or fertility problems, loss of libido or infertility, and erectile or ejaculatory dysfunction (diminished erectile quality and frequency; diminished early morning erections; decreased or watery [mjhid.org]

• Fear

  Arch Dis Child. 1982 Jan; 57 (1):6–12. [ PMC free article ] [ PubMed ] [ Google Scholar ] Ratcliffe SG, Read G, Pan H, Fear C, Lindenbaum R, Crossley J. Prenatal testosterone levels in XXY and XYY males. [ncbi.nlm.nih.gov]

  The common problem for parents is fear of the unknown. Educating yourself will help you learn how to help your son. Support your son. [northshore.org]

  Bock attempts to reassure his readers that such a fear was groundless, because there was very little medical evidence to support such claims. [oii.org.au]

  Many people are frightened by the diagnosis, and their fears will color their perceptions of the child. [web.archive.org]

• Withdrawn

  In amniocentesis, a sample of the fluid surrounding the fetus is withdrawn. Fetal cells in the fluid are then examined for chromosomal abnormalities. [web.archive.org]

• Poor Coordination

  These conditions, which are often called "variants of Klinefelter" syndrome usually have more serious problems ( intellectual disability, skeletal problems, and poor coordination) than classic Klinefelter syndrome (47,XXY). [3] Last updated: 2/14/2018 [rarediseases.info.nih.gov]

  In addition to affecting male sexual development, variants of Klinefelter syndrome are associated with intellectual disability, distinctive facial features, skeletal abnormalities, poor coordination, and severe problems with speech. [web.archive.org]

  Sometimes, symptoms are more prominent and may include weaker muscles, greater height, poor coordination, less body hair, breast growth, and less interest in sex. Often it is only at puberty that these symptoms are noticed. [en.wikipedia.org]

  The association of poor coordination and motor slowness, together with a reduced muscle mass and elongation of the limbs, results in a poor athletic ability, more evident during adolescence. [dx.doi.org]

• Cryptorchidism

  We carried out a Pubmed search with the keywords “cryptorchidism”, “cryptorchid testes”, “testes descent”, “CHH”, “CPHD”, “hypopituitarism”, “Kallman”, “isolated HH or idiopathic HH”. [ijpeonline.biomedcentral.com]

  SUMMARY ANSWER: A multitude of different diagnoses underlie DP, and in boys a history of cryptorchidism, small testicular size and slow growth velocity (GV) predict its clinical course. [ncbi.nlm.nih.gov]

  Cryptorchidism is associated with an increased risk of testicular cancers. This risk nearly doubles when cryptorchidism is bilateral. Orchiopexy will reduce, but not eliminate the risk for cancer. [omicsonline.org]

• Amenorrhea

  Chronic hydrocephalus, most commonly the result of aqueduct stenosis, is associated with both primary and secondary amenorrhea. Only six cases of secondary amenorrhea have been reported to date. [ncbi.nlm.nih.gov]

  Keywords Hypogonadotropic hypogonadism Ovulation induction Kallmann syndrome Anorexia nervosa Pulsatile GnRH Gonadotropins Leptin HPO axis Stress-induced amenorrhea References 1. Santoro N. Update in hyper- and hypogonadotropic amenorrhea. [link.springer.com]

  Functional hypothalamic amenorrhea (FHA), stress-induced anovulation (SIA), athletic amenorrhea, psychogenic amenorrhea, functional hypothalamic chronic anovulation (FHCA), idiopathic hypothalamic hypogonadism 1. [clinicaladvisor.com]

  Adult-onset amenorrhea: A study of 262 patients. Am J Obstet Gynecol 1986;155:531-43. 8. Brown E, Bain J, Lerner P, Shaul D. Psychological, hormonal, and weight disturbances in functional amenorrhea. Can J Psychiatry 1983;28:624-8. 9. [fertilityscienceresearch.org]

• Primary Amenorrhea

  She is a 20-year-old tall, eunuchoid female referred for evaluation of primary amenorrhea. Spontaneous thelarche occurred at the age of 15 years. Breast and pubic hair were at Tanner stages 3 and 4, respectively. [ncbi.nlm.nih.gov]

  At age of 15 she had primary amenorrhea thus she was referred for an endocrine check-up. [umbalk.org]

  amenorrhea Developmental abnormalities with genitalia ( undescended testes, hypospadias ) Infertility ( ↓ sperm count), impotence, and/or ↓ libido Secondary amenorrhea Examine patient for features of: Klinefelter syndrome : gynecomastia Turner syndrome [amboss.com]

  Males exhibit a lack of muscular development and failure of the voice to deepen, whereas females typically exhibit minimal to a complete lack of breast development coupled with primary amenorrhea. [omicsonline.org]

• Sexual Dysfunction

  Decreased libido and sexual dysfunction are common. [symptoma.com]

  […] group) 14 patients (30.34%) reported sexual dysfunction. [ncbi.nlm.nih.gov]

  Men with AHH have decreased libido and erectile dysfunction ranging from decreased tumescence to complete impotence ; The patient’s sexual partner may be the one to report sexual dysfunction. [jle.com]

  Osteoporosis, increased risk of testicular cancer secondary to cryptorchidism, sexual dysfunction, and infertility are just a few of the sequelae associated with IHH. When diagnosed early, these co morbidities can be reduced or even eliminated. [omicsonline.org]

  Also, HAART, particularly protease inhibitor therapy has been associated with sexual dysfunction in men, but the causal nature of this relation has not been clearly established as many of these patients have normal testosterone levels and some studies [edmcasereports.com]

• Microphallus

  As a result, he had a full-skin exam and was found to have a microphallus, undescended testes, and minimal pubic hair distribution. He had a normal sense of smell. [omicsonline.org]

  The twins manifested with microphallus, cryptorchidism, and deficient postnatal activation of the hypothalamic-pituitary-gonadal axis, findings consistent with IHH. [ncbi.nlm.nih.gov]

Hypogonadism is a clinical diagnosis, but a distinction between hypo- and hypergonadotropic forms of the disease requires an assessment of serum levels of gonadotropins and sex hormones. Specimens obtained from patients suffering from HH typically yield reduced concentrations of pituitary hormones and decreased levels of testosterone and estradiol in men and women, respectively. With regards to the former, most patients show low levels of both FSH and LH, but selective deficiencies have also been reported [11]. Due to circadian variations, testosterone and estradiol levels should be determined in the morning. Border cases require the determination of free testosterone and estradiol concentrations since tightly bound hormones are not bioavailable.

The benefit of a GnRH stimulation test is questionable since a direct correlation between the presence of GnRH deficiency and FSH and LH responses could not be established [12]. This may be due to the fact that HH patients show distinct patterns of GnRH secretion, e.g., absent pulses, reduced amplitudes or lack of activity. Conduction of a prolonged stimulated intravenous GnRH test may partially compensate for these differences and may thus allow for a distinction of hypothalamic and pituitary disorders. Also, the GnRH test has been used to distinguish HH from a constitutional delay of growth and puberty in adolescents [13].

Multiple hormone deficiencies generally cause more complex clinical symptoms, but an evaluation of the somatotropic axis, thyroid, and adrenal function by measuring serum concentrations of pituitary hormones, insulin-like growth factor 1, thyroid hormones and cortisol is recommended. In a case of multiple hormone deficiencies not otherwise explainable, magnetic resonance imaging may be carried out to investigate whether hypothalamic or pituitary tumors account for this condition.

• Delayed Bone Age

  Furthermore, disturbances of skeletal development may be noted as an overall delayed bone age and a reduced peak bone mass. A growth of pubic and underarm hair may be reduced or absent. [symptoma.com]

  Patients with constitutional delay of puberty typically have delayed growth before puberty and delayed bone age, compatible with the height. [academic.oup.com]

• Testosterone Decreased

  Half of the patients with normal LH had subnormal total testosterone levels. Total testosterone decreased with age ( Figure 3 ), and a negative correlation ( r = −0.50, P < 0.001) was found between these variables. [ncbi.nlm.nih.gov]

Therapy of HH aims at the induction and maintenance of normal development, growth, and fertility, and this is mainly achieved by hormone replacement therapy.

In men, testosterone is used to induce the development of secondary sexual characteristics and to treat sexual dysfunction, but an administration of this hormone is insufficient to increase fertility. In general, monthly injections of long-acting testosterone esters are necessary. Lifelong therapy is required to maintain a eugonadal state and to avoid complications like osteoporosis and anemia. A medical history of prostate cancer or breast cancer, as well as a hematocrit >55%, are absolute contraindications of testosterone replacement therapy [14]. A patient's response to therapy may be evaluated by monitoring basal levels of sex hormones. If so wished, spermatogenesis may be stimulated with gonadotropins. In most cases, a combined regimen of FSH and human chorionic gonadotropin is applied to this end [15]. Some experts recommend the administration of gonadotropins to adolescent HH patients to avoid prolonged treatment cycles in adulthood and to enhance spermatogenesis in the long term. However, such treatment may provoke gynecomastia and loss of efficiency of human chorionic gonadotropin. Pulsatile administration of GnRH constitutes an alternative to exogenous gonadotropin therapy.

Women diagnosed with HH should be provided an estrogen-progesterone replacement, calcium and vitamin D supplementation [1]. Similar to male patients, restoration of fertility requires the application of gonadotropins or GnRH.

Of note, cryptorchidism should be treated surgically with orchidopexy.

HH is associated with developmental delays and sexual dysfunction, which may represent a major psychological burden. Moreover, affected individuals of both genders have increased risks of osteoporosis, fracture, anemia and metabolic disorders [9]. Life quality may be increased significantly with long-term hormone replacement therapy, but compliance with therapeutic regimens may be an issue. Distinct protocols are available to enhance the fertility of affected individuals.

In general, HH may be provoked by any pathology that interferes with hypothalamic or pituitary gland function. As has been indicated above, there are many entities that may impair the release of GnRH or gonadotropins like follicle-stimulating hormone (FSH) and luteinizing hormone (LH). On the one hand, HH may be the result of gene defects. Congenital HH has traditionally been divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and normosmic isolated or idiopathic hypogonadotropic hypogonadism [2]. Sequence anomalies associated with normosmic HH have been described and may affect genes encoding for the GnRH receptor (GNRHR), kisspeptin receptor 1 (KISS1R), tachykinin 3 and tachykinin 3 receptor (TAC3, TACR3), among others [3]. Of note, certain gene defects may be related to both anosmic and normosmic HH. The interested reader is referred to an excellent review on this topic [4]. Owing to the heterogeneity of genotypes associated with HH, their mode of inheritance varies.

Acquired HH may be a symptom of hypothalamic or pituitary gland lesions, e.g., inadequate blood supply, ischemia or stroke; inflammation or infection; trauma; neoplasms like glioma, pituitary adenoma, and carcinoma; brain irradiation. Those disorders may directly affect the hormonal glands, or may be associated with a local increase in pressure that induces a hypothalamic or pituitary malfunction. Because both glands form part of several hormone axes, affected individuals may develop multiple hormonal disorders.

Moreover, HH may be induced by certain drugs, particularly by steroids, opiates, and alcohol [2]. The pathogenesis of steroid-induced HH is similar to that observed in patients who develop hypogonadism as a complication of Cushing's disease. Other systemic disorders possibly associated with HH are hemochromatosis, sarcoidosis and histiocytosis X.

The overall incidence of congenital HH has been estimated to 1-10 in 100,000 live births, with two-thirds of cases associated with Kallmann syndrome and one-third of patients being diagnosed with normosmic HH [2]. Epidemiological data regarding acquired HH are scarce. In general, men are affected by HH about four times more often than women [5], although the causes of this gender predilection are only poorly understood. Despite men being more prone to X-linked disease, few cases of the disease are related to anomalies of the sex chromosomes. It has been suggested that there may be diagnostic bias and that female HH may be underdiagnosed [1].

The hypothalamic-pituitary-gonadal gland hormone axis is composed of the hypothalamus, which releases GnRH, the pituitary gland, which secretes gonadotropins FSH and LH, and gonadal glands, which produce sex hormones. However, in determined developmental stages, gonadotropins are produced in extra-pituitary tissues and independent of stimulation by GnRH. In this context, prenatal gonadal development largely depends on the availability of placental human chorionic gonadotropin. This particularly applies to weeks 1 to 20 of gestation. Although an LH peak may be observed at about 20 weeks of gestation, subsequently, LH levels decrease again [6]. Thus, dysfunction of superior centers involved in postnatal sexual maturation does not necessarily result in hypogonadism at birth [7]. Patients may suffer from congenital HH but present with a history of an unremarkable perinatal period. Patients who do show symptoms at birth or in the neonatal period are generally males presenting with cryptorchidism and inadequate penile and testicular growth, owing to testicular descent, gonadal growth and Leydig and Sertoli cell proliferation being dependent on GnRH and pituitary gonadotropins. The respective period is often referred to as mini-puberty [8].

Symptom onset or exacerbation of gonadotropin and sex hormone deficiency are most frequently observed in puberty. During this developmental stage, maturation and growth of reproductive organs as well as the development of secondary sexual characteristics take place. They depend on the GnRH pulse generator, pituitary gonadotropin secretion and gonadal production of testosterone and estradiol, and thus, HH patients suffer from delayed, arrested or absent pubertal maturation. HH is not to be confounded with delayed male puberty or delayed female puberty due to physiological variance, nutrient deficiencies, overweight/obesity or systemic diseases. In adulthood, gonadotropins and sex hormones play crucial roles in fertility, ovulation and pregnancy. Some patients don't experience any symptoms until they wish to procreate.

No specific measures can be recommended to prevent HH.

Development and function of testes, ovaries, uterus and breasts are regulated by superior hormonal glands. In detail, the gonadal glands are part of the hypothalamic-pituitary-gonadal hormone axis. Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus and prompts the pituitary gland to release gonadotropins. The latter, in turn, bind to their respective receptors in the aforementioned organs and induce maturation and growth. An interruption of this hormone axis thus causes an absolute deficit of gonadotropins and interferes with the development of primary and secondary sexual characteristics. While such a disorder may draw the patient's or parents' attention in early childhood, it is typically not noted until puberty. Under physiological conditions, GnRH and gonadotropin release increase in adolescence, sexual characteristics become pronounced, and failure herein may manifest in form of hypogonadotropic hypogonadism (HH). Affected individuals present with low serum levels of gonadotropins that are insufficient to induce normal gonadal development and growth.

Causes and clinical presentation of HH are manifold and consequently, the following forms of the disease are distinguished [1]:

• Congenital and acquired forms
• Early and late onset of symptoms
• Idiopathic and secondary HH
• Hypothalamic and pituitary disturbances
• Organic and functional deficits

Of note, HH needs to be distinguished from hypergonadotropic hypogonadism. Both HH and hypergonadotropic hypogonadism patients share the characteristic of gonadal underdevelopment because of an interruption of the hypothalamic-pituitary-gonadal gland hormone axis, but the latter is characterized by an intrinsic functional deficit of the gonadal glands, whose response to gonadotropins is impaired. Due to a lack of negative feedback, serum concentrations of gonadotropins increase.

Hypogonadism is a medical term referring to an underdevelopment of the reproductive organs. In general, maturation and growth of testes, ovaries, uterus and breasts, as well as the development of secondary sexual characteristics like stature, musculature, body hair and voice are regulated by hormones. In brief, the hypothalamus produces gonadotropin-releasing hormone (GnRH), and GnRH stimulates the pituitary gland to release gonadotropins, with both hypothalamus and pituitary gland being located intracranially. Gonadotropins bind to receptors expressed by the aforementioned reproductive organs and trigger events like the scrotal descent of testes at birth, testicular growth during infancy, libido and sexual function as well as menstrual bleedings in puberty, and finally fertility, ovulation, and pregnancy in adulthood. If the afore-described hormonal axis is interrupted due to deficiencies of GnRH or gonadotropins, the affected individual suffers from hypogonadotropic hypogonadism. In some cases, this disease is diagnosed in the neonatal period, but most patients don't experience any complaints until puberty. Their sexual development is impaired, and in order to re-induce the respective processes, to remedy sexual dysfunction and to increase fertility, patients may receive hormone replacement therapy. This therapy should be continued throughout life since hormonal disbalances may cause complications like osteoporosis and anemia. Indeed, osteoporosis is a well-known disease in postmenopausal women, precisely due to decreasing levels of sex hormones.

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15. Zacharin M, Sabin MA, Nair VV, Dabadghao P. Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes normal testicular growth and may promote early spermatogenesis. Fertil Steril. 2012; 98:836-842.