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Autoimmune Disease and Gonadal Failure

Author: Ashni Dharia Author: Catherine Anastasopoulou Editor: Manvinder Singh Updated: 2/15/2025 1:08:36 PM

Introduction

Autoimmunity arises from the dysregulation of immune homeostasis, where the immune system's ability to differentiate between self and non-self tissues becomes compromised, leading to the production of self-reactive lymphocytes and antibodies. An intriguing dimension of autoimmunity is its connection to gonadal failure, termed autoimmune oophoritis in females and autoimmune orchitis in males. The ovaries in females and testes in males are essential organs for hormonal and gamete production, which are crucial for reproductive function. However, in cases of autoimmunity, the body may erroneously target these reproductive organs, leading to inflammation and tissue damage. Such occurrences significantly affect fertility, hormonal balance, and overall health.

Etiology

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Etiology

Autoimmune diseases can increase the risk of gonadal failure due to underlying mechanisms of genetic predisposition, dysregulated immune responses, and environmental triggers. Gonadal failures should be considered in patients with primary endocrine autoimmune diseases such as Hashimoto's thyroiditis, Graves Disease, Addison disease, type 1 diabetes, or autoimmune polyendocrine syndromes.[1] Several non-endocrine autoimmune disorders have also been associated with gonadal failure, including idiopathic thrombocytopenic purpura, vitiligo, Crohn disease, Sjorgen syndrome, primary biliary cirrhosis, myasthenia gravis, triple H syndrome, rheumatoid arthritis, and systemic lupus erythematosus.[1][2][3]

Genetic predisposition plays a significant role in autoimmune gonadal failure. A prominent example is autoimmune polyendocrine syndrome type 1, which is mainly linked to autoimmune regulator (AIRE) gene mutations. The AIRE gene is crucial for maintaining self-tolerance by preventing T-cell attacks on the body's tissues. Mutations in this gene can lead to a loss of self-tolerance, leading to autoimmune gonadal failure. In addition to gonadal failure, some typical associations of autoimmune polyendocrine syndrome type 1 include primary adrenal insufficiency, mucocutaneous candidiasis, and hypoparathyroidism. Autoimmune polyendocrine syndrome type 2 includes autoimmune adrenal insufficiency, thyroid disease, and type 1 diabetes.[4][5]

In autoimmune oophoritis, immune dysregulation is characterized by lymphocytic infiltration of ovarian theca cells in the developing follicles and corpus luteum, usually sparing primordial follicles. This process involves T-cell–mediated injury, an increase in anti-oocyte antibodies producing B cells, and a decrease in the number and activity of natural killer cells, which can mistakenly identify the ovarian tissues as foreign or damaged bodies. Anti-oocyte antibodies can act against hormone-producing cells, the corpus luteum, the zona pellucida, granulosa cells, or oocytes. These antibodies can also target steroid enzymes such as 17 alpha-hydroxylase and 21-hydroxylase or the beta subunit of follicle-stimulating hormone (FSH).[6][7] As a result of all these immune mechanisms, there is a disruption in the hormonal balance, leading to decreased levels of estrogen or testosterone and increased levels of gonadotropins due to subsequent feedback regulation.[8]

Environmental factors, such as chemical exposure, infections, and organic compounds, can trigger gonadal failure in autoimmune diseases.[1] Continued research into the factors contributing to gonadal failure in autoimmune diseases holds promise for improved diagnostic accuracy and, ultimately, better treatment outcomes.

Epidemiology

Premature ovarian insufficiency (POI) is diagnosed when the ovaries stop functioning normally before age 40, resulting in secondary amenorrhea. Secondary amenorrhea occurs when menstruation stops for at least 3 months in women with regular periods, or for at least 3 times the length of the woman's previous menstrual cycles in women who had periods in different intervals. In addition, FSH levels >40 mIU/mL on 2 occasions at least 1 month apart indicate premature ovarian insufficiency. The prevalence of autoimmune premature ovarian insufficiency among cases of idiopathic premature ovarian insufficiency ranges from 4% to 30% in different studies.[9][10] In a large European study, 4.5% of idiopathic premature ovarian insufficiency cases were found to be autoimmune due to the presence of ovarian autoantibodies.[10] The wide range reported in literature reflects differences in study populations and the assays used for autoantibody detection. The prevalence of autoimmune premature ovarian insufficiency in the general female population is estimated to be around 1% to 2%.[11] Autoimmune premature ovarian insufficiency is more common in women with other autoimmune diseases such as Addison disease, hypothyroidism, diabetes mellitus, systemic lupus erythematosus, and rheumatoid arthritis.[9][11] Up to 20% of women with autoimmune Addison disease may develop premature ovarian insufficiency.[11]

Current data fail to provide comprehensive population-level prevalence or incidence estimates of autoimmune gonadal failure, specifically in the male population. The information focuses on specific subgroups of patients but does not cover the broader epidemiology in the general population. In a study, 61% of 13 males with untreated hypogonadism were found to have rheumatic or autoimmune diseases.[12] Another study, which focused specifically on patients with autoimmune Addison disease and the presence of steroidogenic enzyme autoantibodies, found steroidogenic enzyme autoantibodies in 24.7% of male patients with autoimmune Addison disease.[13] Although autoimmune diseases and autoantibodies such as steroidogenic enzyme autoantibodies are relatively common in males, frank autoimmune gonadal failure leading to hypogonadism appears to be rare.[13] The testis seems to be protected from autoimmune damage despite the presence of autoantibodies.

Further epidemiologic studies are required to accurately quantify the burden of autoimmune-mediated gonadal failure in males and females.

Histopathology

The key histopathologic findings of autoimmune gonadal failure in females usually include lymphocytic infiltration of ovaries consisting of CD4+ and CD8+ T cells and plasma B cells.[14] These cells target the developing follicles and corpus luteum, but sparing primordial follicles.[15] In advanced cases, this can result in a fibrotic appearance due to follicle depletion.

In autoimmune orchitis, findings may include lymphocytic infiltration of CD4+ and CD8+ T cells and plasma B cells in seminiferous tubules and testicular interstitium. This condition can disrupt the seminiferous tubules and cause granulomatous inflammation in the testicular parenchyma.[16]

History and Physical

This section outlines the key symptoms and physical examination findings of gonadal failure associated with autoimmune diseases in both females and males, highlighting areas where symptoms overlap with other autoimmune conditions.

Key Symptoms and Physical Signs of Gonadal Failure in Females

  • Symptoms
    • Irregular menstrual periods (oligomenorrhea) or absence of periods (amenorrhea)
    • Abdominal cramping, bloating, nausea, and vomiting
    • Vaginal dryness and decreased libido
    • Mood changes, such as depression and anxiety, and sleep disturbances
    • Vasomotor instability, such as hot flashes and night sweats
    • Altered urinary frequency
    • Dyspareunia [1]
  • Physical examination findings
    • Breast atrophy
    • Loss of pubic and axillary hair
    • Thinning of the vaginal epithelium and decreased vaginal lubrication
    • Dry skin [15]

Key Symptoms and Physical Signs of Gonadal Failure in Males

  • Symptoms
    • Decline in brain concentration on tasks
    • Erectile dysfunction and decreased libido
    • Hot flashes
    • Muscle weakness and loss of muscle mass
    • Depression and irritability
    • Pain and tenderness in the testis
    • Infertility [8]
  • Physical examination findings
    • Small and firm testes
    • Gynecomastia
    • Absence or reduction in sperm production
    • Decreased body and facial hair [17]

Overlapping Findings

  • Fatigue and joint pain
  • Skin rashes
  • Other physical examination findings associated with other autoimmune diseases, such as goiter in cases of thyroid problems or hyperpigmentation in patients with Addison disease.

When evaluating patients with the above symptoms and physical examination findings, obtaining a detailed medical history is essential. This history should focus on:

  • Patient's personal history of autoimmune disorders or genetic conditions
  • Family history of autoimmune disorders
  • Reproductive history, including infertility, pregnancies, age at menarche or menopause for females, and menstrual cycle regularity
  • Environmental exposures
  • Infections
  • Medications
  • History of pelvic chemotherapy and radiation therapy 
  • Previous history of gonadal surgeries

All his information can help evaluate the potential autoimmune etiology of gonadal failure and guide workup and management.

Evaluation

Evaluating gonadal failure involves a comprehensive array of laboratory tests, imaging studies, autoantibody detection, and possibly genetic testing to diagnose the condition and guide appropriate treatment strategies more accurately.

Hormonal Assays

  • FSH (follicle-stimulating hormone) and LH (luteinizing hormone) levels and testosterone (males) or estrogen levels (females)
    • Decreased production of sex hormones, such as testosterone and estrogen, and increased levels of gonadotropins, such as FSH and LH, due to the feedback mechanism suggest a primary cause of gonadal failure.[18] Repeat testing in 4 to 6 weeks is recommended for confirmation.
  • Anti-Müllerian hormone and inhibin B levels (females)
    • Decreased levels suggest reduced ovarian follicular reserve, which provides insights into decreased fertility.[18]
  • Prolactin levels
    • Elevated levels suggest hyperprolactinemia, which can inhibit gonadotropin-releasing hormone secretion and subsequently affect gonadal function.[19]
  • Sex hormone-binding globulin
    • Estrogens increase sex hormone-binding globulin, whereas testosterone decreases sex hormone-binding globulin.[20]
  • Thyroid function tests
    • Evaluate for thyroid dysfunction (autoimmune thyroiditis or Graves disease) to detect potential autoimmune abnormalities.[21]
  • Adrenal antibodies and adrenocorticotropic hormone (ACTH) stimulation test
    • Evaluate for autoimmune adrenal insufficiency (Addison disease) to detect potential autoimmune etiologies.[21]
  • Other autoantibody tests
    • Based on clinical presentation, antinuclear antibodies and rheumatoid factors are used to screen additional autoimmune disorders.[21]

Autoantibody Detection

  • Adrenal antibodies
    • Predictive of autoimmune gonadal failure due to the presence of steroidal cell antibodies, indicating a high risk of developing adrenal insufficiency. The ACTH stimulation test should be repeated yearly.[22]
  • Anti-oocyte and anti-sperm antibodies
    • Although these antibodies lack specificity and sensitivity, they may help detect autoimmune gonadal failure.[23]

Genetic Testing

  • Karyotype analysis
    • To rule out chromosomal abnormalities such as Turner syndrome or Klinefelter syndrome.[18]
  • Gene mutation analysis
    • Mutations in genes, such as the AIRE gene, associated with autoimmune polyglandular syndromes to understand genetic predispositions.[21]

Imaging Studies

  • Pelvic and scrotal ultrasonography
    • Visualizes ovarian or testicular morphology and identifies features suggestive of gonadal failure or abnormalities, such as enlarged cystic ovaries in females.[18]
  • Magnetic resonance imaging (MRI) or computed tomography scan (abdomen or pelvis)
    • Evaluate structural abnormalities or assess the extent of gonadal damage, especially in suspected ovarian or testicular pathology.[18]
  • MRI of the pituitary and hypothalamus
    • Rule out secondary hypogonadism and assess for pituitary or hypothalamic dysfunction.[18]

Other Tests

  • Pregnancy test (urine or serum beta hCG)
    • Essential for women of reproductive age presenting with gonadal failure who are amenorrheic.
  • Bone mineral density (dual-energy x-ray absorptiometry) scan
    • Evaluate for osteoporosis or low bone mass secondary to hormonal deficiency.
  • Complete blood count
    • Evaluate for any signs of anemia, sometimes associated with underlying chronic conditions affecting gonadal function.
  • Comprehensive metabolic panel
    • To assess metabolic disturbances, particularly in conditions such as diabetes mellitus, and electrolyte imbalances affecting gonadal function. Evaluate hepatic and renal function, which may impact hormone metabolism and clearance.
  • Iron studies
    • Serum iron, total iron-binding capacity, and ferritin to assess iron status and rule out iron deficiency anemia or hemochromatosis, which can affect overall health and potentially impact gonadal function.
  • Semen analysis 
    • Evaluate semen volume, sperm count, motility, morphology, and other parameters to assess fertility potential in males presenting with infertility or suspected gonadal failure.
  • Ovarian or testicular biopsy
    • The confirmatory gold standard for diagnosis shows ovarian lymphocytic infiltration; however, it is not routinely recommended due to the associated risks of the biopsy procedure. Moreover, in the majority of the cases, the medical management is unlikely to change after the biopsy.[18][24]

Treatment / Management

Although managing concomitant autoimmune diseases shows promise in some cases of gonadal failure, robust evidence and established treatment protocols are lacking. 

In females with autoimmune gonadal failure, it is important to encourage patients to maintain an active lifestyle, engage in regular exercise, and avoid smoking. Hormone replacement therapy with estrogen and progesterone is the primary treatment to alleviate symptoms of estrogen deficiency, such as hot flashes and vaginal dryness, and also to help prevent osteoporosis.[25][26] However, hormone replacement therapy does not address the underlying autoimmune cause. Immunosuppressive therapy with glucocorticoids, such as prednisolone, may be considered in well-defined cases of autoimmune ovarian failure with active lymphocytic oophoritis.[25] The goal is to suppress the autoimmune attack on the ovaries and potentially achieve temporary restoration of ovarian function and fertility.[12][25] Evidence on the efficacy and safety of immunosuppressants in autoimmune ovarian failure is limited, primarily based on anecdotal case reports, with no prospective randomized controlled trials evaluating this approach.[12][25] Other approaches include treatment of associated autoimmune disorders, ovulation induction, and assisted reproductive techniques such as in vitro fertilization if the residual ovarian function exists. These approaches have very low to dismal success rates.[25] Psychological counseling to address issues such as infertility, anxiety, and depression should always be offered.

In males with autoimmune gonadal failure, testosterone replacement therapy may be used for the symptomatic treatment of male hypogonadism, but it does not address any potential autoimmune etiology.[26] There are some case reports of male hypogonadism associated with autoimmune diseases such as systemic lupus erythematosus, scleroderma,  and rheumatoid arthritis.[12] In such cases, treatment likely involves managing the underlying autoimmune disorder. Other therapies include testicular biopsy or aspirations with assisted reproductive techniques such as intracytoplasmic sperm injection. 

Differential Diagnosis

Other causes of gonadal failure are as follows:

  • Chromosomal abnormalities
    • Klinefelter syndrome: 47XXY (Male)
    • Turner syndrome: 45XO (Female)
    • Trisomy X: 47XXX (Female) [27][28]
  • Genetic abnormalities 
    • Inhibin gene mutation [29]
    • Gonadotropin receptor dysfunction: LHCGR mutation [30]
    • Blepharophimosis-ptosis-epicanthus inversus syndrome: FLOXL2 gene mutation [31]
    • Fragile X syndrome: FMR1 gene mutation [32]
    • Ataxia telangiectasia: ATM gene mutation
    • Bloom syndrome: BLM gene mutation [33]
    • Fanconi anemia: FA gene complex mutation [34]
    • Myotonic dystrophy: DMPK/CNBP gene mutation [35]
    • FSH receptor mutation [36]
  • Enzyme deficiency
    • Steroidogenic enzyme defect
    • 17-alpha-hydroxylase deficiency [37]
    • Galactosemia [38]
  • Developmental abnormalities
    • Cryptorchidism
  • Infections
    • Mumps [39]
    • Varicella
    • Tuberculosis [40]
    • Cytomegalovirus [41]
    • Shigella
    • AIDS
  • Iatrogenic
    • Radiation therapy
    • Ketoconazole
    • Alkylating agents, such as cyclophosphamide and ifosfamide
  • Traumatic
    • Ovarian torsion [42]
    • Testicular torsion [43]
  • Systemic diseases
    • Hepatic cirrhosis 
    • Chronic renal failure 
  • Infiltrative diseases
    • Hemochromatosis 
    • Histiocytosis [44]
    • Granulomatous diseases 

Staging

Table 1. Ovarian Failure

Clinical State

FSH Levels

Estrogen Levels

Menses

Fertility

Subclinical POI

 Normal or slightly elevated

Normal or slightly decreased

Regular

Reduced

Early POI

 Elevated

Decreased

Irregular

Significantly reduced

Overt POI

Elevated

Decreased

Significantly irregular

Infertility

Advanced POI

Very high

Very low

Amenorrhea

Infertility

FSH (follicle-stimulating hormone), POI (premature ovarian insufficiency)[45]

Table 2. Testicular Failure

Clinical State

Testosterone Levels

FSH and LH Levels

Fertility

Subclinical

Low normal or slightly decreased

Normal or slightly elevated

Normal

Early failure

Moderately decreased

Elevated

Decreased sperm count and motility

Overt failure

Slightly decreased

Markedly elevated

Oligospermia/azoospermia

Advanced failure

Very low

Very high

No sperm production

FSH (follicle-stimulating hormone), LH (luteinizing hormone)[46]

Prognosis

The negative impact of autoimmune diseases is well-studied in women as these diseases are more common in females. However, their effects on male reproductive health have not been well-studied.[47] There is a variable clinical course of premature ovarian insufficiency in up to 50% of females, even years after diagnosis. Approximately 20% of women have intermittent spontaneous ovulation with decreasing frequency over time. Only 5% to 10% of these patients can carry the pregnancy to delivery.[1] According to several studies, there is a potential infertility risk derived from autoimmune diseases and autoimmune disease-related drugs in males. Hence, some authors suggest sperm cryopreservation in such cases.[47]

Complications

The complications arising from autoimmune gonadal failure in males include:

  • Delayed puberty [48]
  • Oligospermia or Azoospermia [49]
  • Decreased muscle mass and body hair [50]
  • Hot flashes in severe hypogonadism [51]
  • Increased risk of mood disorders such as depression and anxiety and overall decreased quality of life [52]
  • Erectile dysfunction with reduced ejaculatory volume

The complications arising from autoimmune gonadal failure in females include:

  • Skin atrophy and hair loss [53]
  • Vaginal dryness leading to dyspareunia
  • Osteopenia and osteoporosis [54]
  • Increased cardiovascular morbidity and mortality from coronary artery disease and stroke [55]
  • Increased risk of mood disorders, such as depression and anxiety, and decreased quality of life [52]
  • Increased risk of Parkinson disease, dementia, and cognitive decline
  • Pelvic organ collapse and increased risk of urinary tract infection

Deterrence and Patient Education

Educating patients about autoimmune gonadal failure is crucial for understanding its symptoms, complications, and treatment options. This condition, characterized by the immune system attacking the ovaries or testes, requires lifelong hormone replacement therapy to maintain proper hormone levels and prevent complications such as osteoporosis, cardiovascular disease, and psychological issues.[56] Patients should also be informed about the potential association with other autoimmune disorders, necessitating regular check ups and screening by their physicians. In addition, there is an increased risk of adrenal insufficiency (Addison disease), requiring awareness of symptoms of adrenal crisis. Encouraging regular follow-up visits for hormone level monitoring, medication adjustments, and screening for associated autoimmune disorders is crucial.[12][57] Lifestyle modifications, support resources, and genetic counseling should be emphasized to empower patients to manage their condition effectively and make informed healthcare decisions.[58][59]

Enhancing Healthcare Team Outcomes

In addressing autoimmune gonadal failure, a comprehensive and multidisciplinary approach among healthcare professionals is paramount to enhance patient-centered care, optimize outcomes, ensure patient safety, and improve team performance. Clinicians, advanced practitioners, pharmacists, and other healthcare providers caring for patients with autoimmune gonadal failure must possess a diverse skill set and specialized knowledge to diagnose and manage this condition effectively.[60] Healthcare professionals should be proficient in recognizing the diverse clinical manifestations, understanding the complexities of hormone replacement therapy, and identifying potential comorbidities and associated autoimmune disorders. Moreover, a strategic approach guided by evidence-based practices is essential to tailor treatment plans, minimize adverse effects, and optimize long-term outcomes.

Ethical considerations should guide decision-making processes, ensuring informed consent, patient autonomy, and respect for individual choices in treatment options. Each healthcare professional must understand their unique responsibilities and actively contribute to the patient's care plan, fostering collaboration and interprofessional communication. Effective care coordination is critical to streamlining the patient's journey from diagnosis to treatment and follow-up, reducing errors and enhancing patient safety. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can collectively deliver high-quality, patient-centered care for individuals with autoimmune gonadal failure, ultimately improving patient outcomes.

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