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Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism is provoked by lesions of superior centers of the gonadal hormone axis. An insufficient release of gonadotropin-releasing hormone or gonadotropin by the hypothalamus or pituitary gland, respectively, leads to an underdevelopment of primary and secondary sexual characteristics.


Presentation

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
  • 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 (in some cases) Adults: Loss of interest in sex (libido) in men Loss of menstrual periods (amenorrhea) in women Decreased energy and interest in activities Loss of muscle mass in men Weight gain Mood changes Infertility The health care provider[medlineplus.gov]
  • A 21-year male is admitted for short stature. By the age of 3, he suffered 4 surgical procedures for bilateral cryptorchidism without improvement. Around the age of 8, dwarfism was recorded without further investigations.[umbalk.org]
  • Short stature may develop during childhood. Myopia (short sightedness) is common. Treatments for: There is no cure for 4H syndrome; treatment is supportive.[australasianleukodystrophyfoundation.com]
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]
  • XXY individuals are also more likely to develop certain medical conditions, including osteoporosis (weak bones), varicose veins, type 2 diabetes, and heart valve defects.[web.archive.org]
  • Children with Klinefelter syndrome may have weak muscle tone (hypotonia) and problems with coordination that delay the development of motor skills, such as sitting, standing, and walking.[ghr.nlm.nih.gov]
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]
  • 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]
  • 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
  • gain Mood changes Infertility The health care provider will perform a physical exam and ask about your symptoms.[medlineplus.gov]
  • 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 Mood changes Infertility Exams and Tests The health care provider will perform a physical exam and ask about your symptoms.[mountsinai.org]
  • Alternate-day GnRH therapy for ovarian hypofunction induced by weight loss: Treatment of six patients who remained amenorrhoeic after weight gain. Clin Endocrinol (Oxf) 1993;39:641-8. 7. Reindollar RH, Novak M, Tho SP, McDonough PG.[fertilityscienceresearch.org]
Fatigue
  • RESULTS: The patients' mean age ( SD) was 44.3 6.3 years (range 21-67 years) referred for evaluation of low testosterone together with decreased libido, erectile dysfunction, fatigue or tiredness, anxiety, and osteoporosis.[ncbi.nlm.nih.gov]
  • Depression, fatigue, low energy, poor concentration, mild anemia and low bone mineral density with osteoporotic fractures may also occur ( 2 , 3 , 6 , 7 , 8 , 9 , 10 ).[edmcasereports.com]
  • Rarely secondary adrenal insufficiency presents as fatigue and anovulation. Serum dehydroandrosterone sulfate (DHEAS) will be in the lower range for age.[clinicaladvisor.com]
  • […] reasonable for chromosomal karyotyping in those with suspicious clinical findings, negative results of peripheral blood karyotyping, and possible mosaicism. 11 The diagnosis of KS should be considered in men with complaints related to hypogonadism, ie, fatigue[doi.org]
  • This may be due to the less recognizable consequences of testosterone deficiency such as fatigue, low libido, poor concentration, and depression, 12 in addition to currently poorly quantified psychosocial effects of the condition.[dx.doi.org]
Anosmia
  • Abstract The association of anosmia and congenital hypogonadotropic hypogonadism (CHH) is well described; however, congenital arhinia is a malformation associated with CHH that occurs much more rarely.[ncbi.nlm.nih.gov]
  • 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]
  • OBJECTIVE: Congenital hypogonadotropic hypogonadism with anosmia (Kallmann syndrome) or with normal sense of smell is a heterogeneous genetic disorder caused by defects in the synthesis, secretion and action of gonadotrophin-releasing hormone (GnRH).[ncbi.nlm.nih.gov]
  • In around 50-60% of cases, CHH is associated with a variety of non-reproductive abnormalities, most commonly anosmia/hyposmia, which defines Kallmann Syndrome (KS) by its presence.[ncbi.nlm.nih.gov]
  • Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry is necessary to determine reliably whether olfaction is normal or partially defective.[ncbi.nlm.nih.gov]
Decrease in Height
  • The decreased body height in the man, stands, because of his 2 Xp arms, in contrast to the hypothesis about the relevance of the number of SHOX gene copies, but it should be mentioned that Nielsen et al. published the case in 1966 and it is not possible[dx.doi.org]
Hirsutism
  • J Clin Endocrinol Metab 87 : 161 – 165 28 1999 Androgen receptor-mediated hypersensitivity to androgens in women with nonhyperandrogenic hirsutism: skewing of X-chromosome inactivation.[dx.doi.org]
Decreased Libido
  • We describe the case of a 20-yr-old male amateur kickboxer who was admitted to hospital complaining of decreased libido and impotence 2 weeks after an intensive bout.[ncbi.nlm.nih.gov]
  • RESULTS: The patients' mean age ( SD) was 44.3 6.3 years (range 21-67 years) referred for evaluation of low testosterone together with decreased libido, erectile dysfunction, fatigue or tiredness, anxiety, and osteoporosis.[ncbi.nlm.nih.gov]
  • Seven years later, the patient complained of decreased libido, anejaculation and erectile dysfunction. CD4 count (1321.9 cells/µL; reference value 500) was normal.[edmcasereports.com]
  • Decreased libido and sexual dysfunction are common.[symptoma.com]
  • Gynaecomastia or history of gynaecomastia during puberty; decreased libido; history of undescended testes. Learning disability; delayed speech development; behavioural problems; psychosocial disturbances.[patient.info]
Cryptorchidism
  • Micropenis combined with cryptorchidism was the most common phenotype (39%).[ncbi.nlm.nih.gov]
  • 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]
  • We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism.[ncbi.nlm.nih.gov]
  • This case demonstrates that abnormalities of nasal development may provide an early diagnostic clue to hypogonadotropic hypogonadism, particularly in female patients who would not manifest classic signs of CHH in infancy (micropenis and cryptorchidism[ncbi.nlm.nih.gov]
  • All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype.[ncbi.nlm.nih.gov]
Amenorrhea
  • Resolution of the amenorrhea was observed to occur following 3rd ventriculostomy.[ncbi.nlm.nih.gov]
  • We described a case of singleton pregnancy in a 38-year-old patient, presenting with primary hypogonadotropic amenorrhea and empty sella syndrome, treated with human menopausal gonadotropins and performing intrauterine insemination in first attempt.[ncbi.nlm.nih.gov]
  • PATIENT(S): A young woman with persistent amenorrhea, symptomatic hypogonadotropic hypogonadism, and hyperprolactinemia. INTERVENTION(S): Tamoxifen was administered in addition to bromocriptine.[ncbi.nlm.nih.gov]
  • Functional hypothalamic amenorrhea (FHA), stress-induced anovulation (SIA), athletic amenorrhea, psychogenic amenorrhea, functional hypothalamic chronic anovulation (FHCA), idiopathic hypothalamic hypogonadism 1.[clinicaladvisor.com]
  • 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]
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]
  • The patient was a 19-year-old female who presented the nIHH phenotype with primary amenorrhea, cleft lip and palate, mixed hearing disorders, and skeletal malformations.[ncbi.nlm.nih.gov]
  • At age of 15 she had primary amenorrhea thus she was referred for an endocrine check-up.[umbalk.org]
  • 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.[symptoma.com]
Sexual Dysfunction
  • […] group) 14 patients (30.34%) reported sexual dysfunction.[ncbi.nlm.nih.gov]
  • Decreased libido and sexual dysfunction are common.[symptoma.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]
  • 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]
Microphallus
  • The twins manifested with microphallus, cryptorchidism, and deficient postnatal activation of the hypothalamic-pituitary-gonadal axis, findings consistent with IHH.[ncbi.nlm.nih.gov]
  • 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]

Workup

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]

Treatment

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.

Prognosis

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.

Etiology

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.

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

No specific measures can be recommended to prevent HH.

Summary

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.

Patient Information

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.

References

Article

  1. Silveira LF, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013; 98(5):1781-1788.
  2. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics. 2013; 68(S1):81-88.
  3. Francou B, Bouligand J, Voican A, et al. Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations. PLoS One. 2011; 6(10):e25614.
  4. Valdes-Socin H, Rubio Almanza M, Tome Fernandez-Ladreda M, Debray FG, Bours V, Beckers A. Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. Front Endocrinol. 2014; 5:109.
  5. Seminara SB, Hayes FJ, Crowley WF, Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev. 1998; 19(5):521-539.
  6. Choi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles. Gynecol Endocrinol. 2014; 30(3):174-181.
  7. Kumar PA, Pitteloud N, Andrews PA, et al. Testis morphology in patients with idiopathic hypogonadotropic hypogonadism. Hum Reprod. 2006; 21(4):1033-1040.
  8. Lambert AS, Bougneres P. Growth and descent of the testes in infants with hypogonadotropic hypogonadism receiving subcutaneous gonadotropin infusion. Int J Pediatr Endocrinol. 2016; 2016:13.
  9. Laitinen EM, Hero M, Vaaralahti K, Tommiska J, Raivio T. Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism. Int J Androl. 2012; 35(4):534-540.
  10. Khera M, Broderick GA, Carson CC, et al. Adult-Onset Hypogonadism. Mayo Clin Proc. 2016; 91(7):908-926.
  11. Layman LC, Porto AL, Xie J, et al. FSH beta gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endocrinol Metab. 2002; 87(8):3702-3707.
  12. Waal HD-VD. Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects. Eur J Endocrinol. 2004; 151(Suppl 3):U89-94.
  13. Prasad HK, Khadilkar VV, Jahagirdar R, Khadilkar AV, Lalwani SK. Evaluation of GnRH analogue testing in diagnosis and management of children with pubertal disorders. Indian J Endocrinol Metab. 2012; 16(3):400-405.
  14. Carnegie C. Diagnosis of hypogonadism: clinical assessments and laboratory tests. Rev Urol. 2004; 6(Suppl 6):S3-8.
  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.

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Last updated: 2018-06-21 19:47