Hypogonadism resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Hypogonadism is a disorder of the reproductive system which results in lack of function of the gonads (ovaries or testes). Hypogonadism is caused by several conditions which may be congenital, acquired, genetic, or malignancies. Hypogonadism may be classified on the basis of etiology and the site causing the defect into primary or secondary hypogonadism. Primary hypogonadism results from defect in the gonads themselves and it has a high level of the gonadotropin hormones FSH and LH. Secondary hypogonadism indicates a defect in the pituitary gland or the hypothalamus and presents with a low level of the gonadotropin releasing hormone, FSH, and LH. Hypogonadism is also associated with low level of testosterone hormone, especially in the males. Genetic mutations that can cause hypogonadism include ANOS 1, SOX10, SEMA3A, IL17RD and FEZF1. Other genes include KISS, GNRNH, and PROK. Hypogonadism must be differentiated from diseases that cause delayed puberty or infertility. The prevalence of hypogonadism is estimated to be 38,700 per 100,000 individual aging 45 years. The incidence of hypogonadism is 1230 per 100,000 persons. Hypogonadism affects men more than women and its prevalence increases with age. Hypogonadism has many risk factors like dyslipidemia, obesity, malignancies and alcohol intake. Screening may be done for men patients who present with erectile dysfunction, infertility, HIV patients and young patients with osteoporosis. If left untreated, patients with hypogonadism will end up with infertility and rheumatic autoimmune diseases. Hypogonadism can cause complications like gynecomastia and delay of puberty in the prepubertal patients. It can also cause depression and cardiovascular stroke in the adults. Hypogonadism usually has a good prognosis with the proper treatment. Patients with hypogonadism usually present with loss of the secondary sexual characteristics. Male patients present with infertility, loss of libido, and erectile dysfunction. Female patients present with amenorrhea and no pubic hair. Lab diagnosis reveals low testosterone levels, variable FSH and LH levels according to the cause of hypogonadism whether primary or secondary. The mainstay of treatment for hypogonadism is testosterone replacement therapy and it can be administrated through different regimens injected, transdermal or buccal. In females, estrogen replacement is helpful besides testosterone.

Causes

Life Threatening Causes

• Astrocytoma
• Chronic renal failure
• Papillary renal cell carcinoma 
• Postinfectious lesions of the central nervous system (CNS)
• Ureter cancer 
• Urinary system cancer 
• Wilms tumor
• Infective endocarditis

Common Causes

• Anorchidism
• Chemotherapy
• Cryptorchidism
• FSH beta subunit mutation (follicle stimulating hormone)
• FSH receptor mutation
• Klinefelter Syndrome
• LH (luteinizing hormone) beta subunit mutation
• LH receptor mutation
• LH resistance
• Radiation therapy
• Sertoli-cell-only syndrome
• Testicular biosynthetic defects
• Autoimmune oophoritis
• Chemotherapy
• Familial and sporadic XX gonadal dysgenesis and its variants
• Familial and sporadic XY gonadal dysgenesis and its variants
• FSH beta subunit mutation (follicle stimulating hormone)
• FSH receptor mutation
• Galactosemia
• Glycoprotein syndrome type 1
• LH (luteinizing hormone) beta subunit mutation
• LH/human chorionic gonadotropin resistance
• LH receptor mutation
• Noonan Syndrome
• Premature menopause
• Polycystic ovarian disease
• Radiation therapy
• Resistant ovary
• Turner Syndrome
• Astrocytoma
• Bardet-Biedl Syndrome
• Congenital adrenal hypoplasia
• Congenital hypogonadotropic hypogonadism
• Craniofacial anomalies
• Craniopharyngioma
• Exercise-induced amenorrhea
• Functional gonadotropin deficiency
• Gaucher Disease
• Germinoma
• Head trauma
• Hyperprolactinemia
• Hypothalamic glioma
• Isolated FSH deficiency
• Isolated LH deficiency
• Kallmann Syndrome
• Langerhans histiocytosis
• Laurence-Moon Syndrome
• Marijuana use
• Optic glioma
• Other germ cell tumors
• Pituitary tumor
• Postinfectious lesions of the central nervous system (CNS)
• Prader-Willi Syndrome
• Radiation therapy
• Vascular abnormalities of the CNS

Diagnosis

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Treatment

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Patients with hypogonadism are treated mainly with sex hormones replacement. Sex hormones will help in retaining the secondary sexual characteristics for both genders. They will also help in maintaining normal bone density and muscle mass. The main medical therapy in males will be testosterone replacement. In the females, estrogen replacement is important besides testosterone.

Medical therapy for men

Testosterone replacement therapy

• Based on endocrine society clinical practice guidelines, testosterone replacement therapy is the mainstay of treatment in patients with hypogonadism.
• Indications of testosterone therapy are as the following:
  • Testosterone is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone.
    • Primary hypogonadism (congenital or acquired): Testicular failure from conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
    • Hypogonadotropic hypogonadism (congenital or acquired): Idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range.
  • Limitations of use:
    • Safety and efficacy of testosterone in males less than 18 years old have not been established.
• Testosterone therapy is contraindicated in the following cases:
  • Breast carcinoma
  • Prostate cancer
  • Patients with hematocrit value more than 50%
  • Untreated obstructive sleep apnea
  • Severe lower urinary tract infections
  • Heart failure
• In this table, the different recommended regimens of testosterone administration are discussed.

Type of testosterone drug	Administrative doses	Adverse effects
Testosterone (Injection)	75-100 mg intramuscular injection per week. 150-200 mg intramuscular injection every two weeks. Subcutaneous implantation of testosterone pellets every 3-6 months.	Injection site reactions
Testosterone (Transdermal)	Testosterone patches: one or two doses of 5 mg on the non-genital skin as the back, thigh and upper arm. Testosterone gel: 1% dose of gel on the non-genital skin.	Transdermal testosterone may be accompanied with the following skin reactions: Pruritis Dermatitis Blisters Erythema Vesicles Acne Hot flushes
Testosterone (Buccal)	30 mg of bioadhesive tablet every 12 hour.	Gum irritation Bitter tasting Toothache Stomatitis

Medical therapy for women

• For women, testosterone administration is also indicated as a treatment for the sexual dysfunction in postmenopausal women. Testosterone is an essential source of estrogen in the postmenopause phase.
• The mainstay medical therapy for the women complaining of hypogonadism will be testosterone and estrogen.

Estrogen replacement therapy

• Indications: treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
• Dosing information: oral tablet, 1 to 2 mg ORALLY daily; titrate and adjust to the lowest dose as necessary to control symptoms.
• Contraindications:
  • Undiagnosed abnormal genital bleeding
  • Known, suspected, or history of breast cancer
  • Known or suspected estrogen-dependent neoplasia
  • Active DVT, PE, or a history of these conditions
  • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
  • Known anaphylactic reaction or angioedema with Climara
  • Known liver impairment or disease
  • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
  • Known or suspected pregnancy

Do's

• The content in this section is in bullet points.

Don'ts

• The content in this section is in bullet points.

References

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