Hypogonadism

Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Hypergonadotropic hypogonadism results when the gonads fail, and hypogonadotropic hypogonadism results from failures in the hypothalamic–pituitary–gonadal axis. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Diagnosis is guided by the history, physical exam, measurement of hormone levels, and an evaluation for an underlying etiology. Management is with hormone replacement.

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Overview

Definition

Hypogonadism is a condition in which there is decreased sex hormone production by the testes or ovaries.

Etiology

  • Hypergonadotropic hypogonadism (primary hypogonadism) in males:
    • Klinefelter syndrome
    • Cryptorchidism
    • Previous chemotherapy or radiotherapy treatment
    • Congenital bilateral anorchia
    • Testicular trauma
    • Gonadectomy
    • Defects in testicular determination: gonadal dysgenesis
    • Sertoli-cell-only syndrome
    • Luteinizing hormone (LH) resistance
    • Mumps virus
    • Disorders of androgen synthesis:
      • 17β-hydroxylase dehydrogenase deficiency
      • 5α-reductase deficiency
      • 17-hydroxylase deficiency
  • Hypergonadotropic hypogonadism (primary hypogonadism) in females:
    • Turner syndrome
    • XX and XY gonadal dysgenesis
    • Premature ovarian insufficiency
    • Autoimmune oophoritis
    • Galactosemia
    • Follicle-stimulating hormone (FSH) receptor gene mutations
    • LH or hCG resistance
    • Noonan syndrome
    • Previous chemotherapy or radiotherapy treatment
  • Hypogonadotropic hypogonadism (secondary hypogonadism): disruption of the hypothalamus or pituitary gland hormonal axis
    • Sarcoidosis
    • Hemochromatosis
    • Tuberculosis
    • Medications:
      • Opioid analgesics
      • Glucocorticoids
      • Leuprolide
    • Hypothalamic or pituitary tumors (pituitary adenoma)
    • Congenital disorders:
      • Kallmann syndrome
      • Prader-Willi syndrome 
      • Angelman syndrome
      • Gaucher disease
    • Other disorders:
      • Eating disorders
      • Exercise-induced hypogonadism
      • Hyperprolactinemia
      • Cushing syndrome
      • HIV/AIDS
      • Morbid obesity
      • Type 2 diabetes mellitus

Epidemiology

  • Hypogonadism may occur at any age.
  • Often underreported
  • Primary hypogonadism:
    • Most common cause in women is Turner syndrome (incidence: 1 in 2000–2500 live births).
    • Most common cause in men is Klinefelter syndrome (incidence: 1 in 600 live male births).
    • Men > women (because incidence of Klinefelter syndrome > incidence of Turner syndrome)
  • Secondary hypogonadism:
    • Less common than primary hypogonadism
    • Incidence: 1 in 10,000–86,000 people
    • Men = women
    • Kallmann syndrome causes approximately ⅔ of congenital cases.

Pathophysiology

Normal physiology

  • The gonads function as part of the hypothalamic–pituitary–gonadal axis, which functions as a feedback loop:
    • A hypothalamic pulse generator in the arcuate nucleus → releases gonadotropin-releasing hormone (GnRH) into the hypothalamic–pituitary portal system 
    • Anterior pituitary secretes FSH and LH → stimulates gonadal activity → sex hormone production (e.g., testosterone, estrogen)
    • ↑ Gonadal hormones → ↓ FSH and LH secretion at the pituitary level → completes a feedback loop
  • In men (testes): 
    • LH → Leydig cells secrete testosterone.
    • FSH → tubular growth
  • In women (ovaries):
    • LH → theca and interstitial cells → produce progestins and androgens
    • FSH → granulosa cells → precursor steroids to estrogen
Summary of the hypothalamic–pituitary–ovarian axis

Summary of the hypothalamic–pituitary–ovarian axis:
The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to release the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The gonadotropins then stimulate the ovary to produce estrogen and progesterone, which in turn lead to endometrial growth and maturation. Any disruption in this pathway could lead to amenorrhea.

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Hypogonadism

Hypogonadism occurs if the hypothalamic–pituitary–gonadal axis is interrupted at any level. 

  • Primary (hypergonadotropic hypogonadism):
    • The gonad is not producing an amount of sex steroid sufficient to suppress LH and FSH.
    • Hormone levels: ↑ LH and FSH (due to lack of feedback), ↓ sex hormone 
  • Secondary (hypogonadotropic hypogonadism): 
    • Occurs from either:
      • Failure of the hypothalamic GnRH pulse generator 
      • Inability of the pituitary to respond by secreting LH and FSH
    • Hormone levels: ↓ GnRH, LH, FSH, and sex hormone
    • Most commonly from malformations in pituitary development or lesions of the pituitary that are acquired.
Pathogenesis of primary versus secondary hypogonadism

Pathogenesis of primary versus secondary hypogonadism:
Primary hypogonadism results from an issue with the testes (or ovaries), resulting in decreased sex hormone despite adequate (or high) levels of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).
In secondary hypogonadism, an issue in the hypothalamus or pituitary gland results in decreased GnRH, LH, and FSH, resulting in decreased sex hormone production (despite normal testes or ovaries).

Image by Lecturio. License: CC BY-NC-SA 4.0

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Clinical Presentation

Clinical presentation will vary depending on the age at onset and sex.

Presentation in men

  • Prepubertal men:
    • Eunuchoidism
    • Sparse body hair
    • Absence or regression of secondary sexual characteristics
    • Voice does not deepen
    • Poor development of skeletal muscle mass
    • Delay in epiphyseal closure → long arms and legs
  • Postpubertal men:
    • Lack of energy
    • ↓ Libido
    • Erectile dysfunction
    • Depression
    • ↓ Muscle mass
    • ↓ Body hair
    • ↓ Bone mass
    • Gynecomastia (more likely in primary hypogonadism)
    • Infertility (↓ sperm count)

Presentation in women

  • Prepubertal women:
    • Failure to progress through puberty
    • Absence or regression of secondary sexual characteristics
    • Primary amenorrhea
  • Postpubertal women:
    • Secondary amenorrhea
    • Infertility
    • Fatigue
    • ↓ Libido

Diagnosis and Management

Laboratory evaluation

Men:

  • Initial testing:
    • ↓ Serum testosterone: 
      • Optimal timing: morning (due to diurnal variation)
      • If abnormal, should be remeasured on 1–2 separate occasions.
    • FSH levels and LH levels allow differentiation between primary and secondary hypogonadism:
      • Increased: primary hypogonadism
      • Decreased: secondary hypogonadism
  • If concerned for primary hypogonadism:
    • Is the etiology known (e.g., chemotherapy, history of mumps orchitis)?
    • If not → karyotype analysis
  • If concerned for secondary hypogonadism:
    • Prolactin
    • Thyroid function
    • Morning cortisol
    • Iron and ferritin levels
    • Genetic testing
  • Fertility evaluation: semen analysis

Women:

  • Always start with a urine pregnancy test or qualitative hCG test to rule out pregnancy.
  • FSH, LH, and estradiol:
    • ↑ FSH and LH, ↓ estradiol: primary hypogonadism
    • ↓ FSH and LH, ↓ estradiol: secondary hypogonadism
  • The evaluation for an etiology is similar to the workup in men.

Imaging

  • MRI of the brain should be considered for: 
    • Pituitary hormone abnormalities (e.g., hyperprolactinemia)
    • Visual field defects
    • Neurologic abnormalities
  • MRI of the pelvis or ultrasound of the ovaries in females with concern for agenesis 
  • Ultrasonography of testes for: 
    • Suspected history of mumps orchitis 
    • Abnormal development of the testes

Management

  • Underlying cause must be treated.
  • Hormonal replacement therapy with the goals of:
    • Promoting development and maintaining secondary sexual characteristics with normal sexual function
    • Building and sustaining normal bone and muscle mass
    • Aid in proper psychosocial adjustment
  • In men: testosterone replacement
  • In women: estrogen replacement
  • Pulsatile GnRH therapy aids fertility in hypogonadotropic hypogonadism.

Clinical Relevance

  • Klinefelter syndrome: chromosomal aneuploidy characterized by the presence of ≥ 1 extra X chromosome in a male karyotype, most commonly leading to the karyotype 47, XXY. Patients present as tall, phenotypic men, with small testes, decreased body hair, gynecomastia, and infertility. Treatment consists of lifelong testosterone replacement therapy.
  • Cryptorchidism: among the most common congenital anomalies in young boys. Typically, this asymptomatic condition presents during a routine well-child examination, where 1 or both testicles are not palpable in the scrotum. If the testis is palpable, but not in the dependent intrascrotal location, management consists of an orchiopexy (bringing the testicle to the scrotum).
  • Pituitary adenomas: tumors that develop within the anterior lobe of the pituitary gland. Nonfunctioning or nonsecretory adenomas do not secrete hormones, but compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type they evolved from, leading to hyperpituitarism. Diagnosis is confirmed with imaging. Management depends on the type of adenoma, but can include surgical resection, radiation, and dopamine agonists.
  • Mumps virus: caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps manifests initially with fever, muscle pain, headache, poor appetite, feeling generally unwell, and parotitis. Complications include meningitis, pancreatitis, deafness, and testicular inflammation, which can result in infertility. The infection is managed with supportive care and is preventable by vaccination.
  • Turner syndrome: genetic condition affecting women, in which an X chromosome is partly or completely missing. The classic result is the karyotype 45,X0 with a female phenotype. Characteristic appearance is that of short stature, webbed neck, broad chest, widely spaced nipples, amenorrhea, and peripheral edema of the hands and feet. Genetic testing confirms diagnosis. Treatment consists of hormone replacement therapy. 

References

  1. Vogiatzi, M. (2019). Hypogonadism treatment & management. Medscape. Retrieved May 7, 2021, from https://emedicine.medscape.com/article/922038-treatment#d7
  2. Snyder, P. (2020). Clinical features and diagnosis of male hypogonadism. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-male-hypogonadism
  3. Snyder, P. (2020). Causes of primary hypogonadism in males. UpToDate. Retrieved May 8, 2021, from https://www.uptodate.com/contents/causes-of-primary-hypogonadism-in-males
  4. Snyder, P. (2020). Causes of secondary hypogonadism in males. UpToDate. Retrieved May 8, 2021, from https://www.uptodate.com/contents/causes-of-secondary-hypogonadism-in-males
  5. Welt, C., Barbieri, R. (2020). Evaluation and management of primary amenorrhea. UpToDate. Retrieved May 8, 2021, from https://www.uptodate.com/contents/evaluation-and-management-of-primary-amenorrhea
  6. Welt, C., Barbieri, R. (2020). Epidemiology and causes of secondary amenorrhea. UpToDate. Retrieved May 9, 2021, from https://www.uptodate.com/contents/epidemiology-and-causes-of-secondary-amenorrhea
  7. Hirsch, I.H. (2021). Male hypogonadism. MSD Manual Professional Version. Retrieved June 15, 2021, from https://www.msdmanuals.com/professional/genitourinary-disorders/male-reproductive-endocrinology-and-related-disorders/male-hypogonadism
  8. Sizar, O., Schwartz, J. (2020). Hypogonadism. StatPearls. Retrieved June 15, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK532933/

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