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An intriguing connection is emerging between two seemingly disparate conditions: premature ovarian insufficiency (POI) and Hashimoto’s thyroiditis. This autoimmune thyroid disorder, characterized by an attack on the thyroid gland, has been linked to a heightened risk of diminished ovarian reserve and premature depletion of ovarian follicles, known as POI. As researchers delve deeper into this association, a concerning pattern unfolds – women with Hashimoto’s face a higher risk of experiencing menopausal symptoms and infertility due to ovarian failure at a younger age. In this Q&A article, we’ll look at the interplay between these two conditions, shedding light on the mechanisms that underlie this connection and the diagnosis, management, and potential therapeutic strategies.

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Premature ovarian insufficiency (POI), also known as premature ovarian failure, is a condition characterized by the loss of normal ovarian function before the age of 40 years. It affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old.

POI is characterized by amenorrhea (the absence of menstruation) with low estrogen levels and high levels of gonadotropins, which, in some cases, leads to loss of fertility. The condition is also associated with a decrease in ovarian follicles and a lack of hormone secretion.

The global overall prevalence of POI is estimated to be 3.5% of women. The highest prevalence is found in North America (11.3%), and the prevalence has been increasing slightly over the past 20 years.

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The risk factors for POI are diverse and can be categorized into genetic, autoimmune, environmental, and iatrogenic (caused by medical treatment) factors. Here are the primary risk factors.

Genetic factors

• Family history: Women who have a mother or sister with POI are at a higher risk.
• Genetic disorders: Conditions like Fragile X syndrome or Turner syndrome increase the risk of POI.

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Autoimmune diseases

Autoimmune disorders, where the body’s immune system attacks its own tissues, can affect ovarian function and lead to POI.

Environmental factors

• Smoking: Exposure to cigarette smoke has been associated with an earlier onset of POI.
• Chemicals and toxins: Exposure to certain chemicals and environmental toxins may contribute to the development of POI.

Iatrogenic factors

• Cancer treatments: Chemotherapy and radiation therapy, especially pelvic irradiation, are significant risk factors due to their gonadotoxic effects.
• Surgery: Ovarian or pelvic surgeries that impact the ovaries can lead to POI.

Other factors

• Age: The risk increases as a woman approaches the typical age range of 35-40 years, although POI can occur in younger women and even teenagers.
• Irregular menstrual history: Women with a history of irregular menstruation may have a higher predisposition to developing POI.

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The symptoms of POI are due to the decreased production of estrogen and other hormones and are similar to those of perimenopause or menopause. Symptoms can vary in severity and include:

• Irregular or missed periods: One of the earliest signs of POI is irregular menstrual cycles or periods that stop altogether (amenorrhea). Irregularity can persist for years and may start after a pregnancy or stopping birth control pills.
• Hot flashes and night sweats: Sudden feelings of heat, often in the upper body, which can cause sweating and discomfort, similar to menopausal hot flashes.
• Vaginal dryness: Reduced estrogen levels can lead to dryness of the vaginal tissues, causing discomfort during sexual intercourse and increased risk of infections.
• Mood swings and depression: Hormonal changes can affect mood, leading to irritability, mood swings, anxiety, and depression.
• Decreased libido: Reduced hormone levels can result in a decreased interest in sexual activity.
• Sleep disturbances: Insomnia or trouble sleeping can occur due to hormonal imbalances and night sweats. Frequent waking can also be a problem.
• Cognitive changes: Some women experience difficulties with concentration, memory, and overall cognitive function.
• Infertility: One of the most significant symptoms of POI is difficulty in conceiving due to the reduced function of the ovaries.
• Bone density loss: Low estrogen levels can lead to decreased bone density, increasing the risk of osteoporosis and fractures.
• General symptoms: Fatigue, joint pain, and muscle aches can also be present.

These symptoms can vary in intensity and may not be present in all women with POI. Some women with POI may still have periods and may even get pregnant, which can sometimes lead to delayed diagnosis.

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POI is diagnosed when a woman stops menstruating before age 40, along with testing results that show an elevated serum level of pituitary gonadotropin follicle-stimulating hormone (FSH) and low levels of estradiol (E2). Serum levels of FSH and E2 are measured on at least two separate occasions with more than a four-week interval. Patients who have continuously elevated FSH levels (greater than 25 IU/L) are diagnosed with POI. It’s important to note that while the condition was previously referred to as premature ovarian failure (POF), the term POI is now preferred as some patients are known to have residual ovarian function that occasionally leads to pregnancy.

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For women with POI, hormone replacement therapy (HRT) with estrogen is strongly recommended to treat symptoms of estrogen deficiency and prevent long-term health risks. The specific recommendations are:

• Estrogen therapy, either oral or transdermal, to achieve physiological estrogen replacement levels. This helps relieve vasomotor symptoms like hot flashes, prevents bone loss and osteoporosis, and reduces risks of cardiovascular disease and urogenital atrophy.
• Combined estrogen-progestin therapy for women who have not had a hysterectomy, to protect the endometrium from unopposed estrogen exposure and reduce cancer risk.
• Consideration of low-dose testosterone therapy, in addition to estrogen, to improve sexual function, well-being, and bone mineral density, especially if the patient has symptoms of androgen deficiency.
• Continuing HRT until the average age of natural menopause around 50-51 years old, as the health risks associated with HRT in older postmenopausal women do not apply to the prematurely estrogen-deficient state of POI.

The route of administration (oral vs transdermal) and specific formulations can be individualized based on patient preference, contraceptive needs, metabolic factors, and risk profiles. Overall, HRT regimens that most closely mimic normal ovarian hormone production are recommended for women with POI.

Calcium and vitamin D supplements are recommended to help prevent osteoporosis, as women with POI have a higher risk due to low estrogen levels.

Other treatments focus on managing associated conditions like osteoporosis, heart disease, depression, and anxiety that can arise from POI.

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For women with POI who want to become pregnant, there are a few options:

• Spontaneous pregnancy: Around 5 to 10% of women with POI can still get pregnant spontaneously without any treatment, as they may experience intermittent ovulation. However, this is rare.
• In vitro fertilization (IVF) with donor eggs: This is considered the most effective treatment option for women with POI who want to get pregnant. Donor eggs from another woman are fertilized with the partner’s sperm, and the resulting embryo is transferred to the woman’s uterus. Success rates with donor eggs can be as high as 75%.
• IVF with own eggs (if any remaining): For women who have frozen their eggs before POI onset or those with a few remaining high-quality eggs, IVF can be attempted using their own eggs along with fertility medications.

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Several lifestyle interventions can help manage the symptoms of POI:

Diet and supplements

• Consuming foods rich in antioxidants like fruits, vegetables, and whole grains may help reduce oxidative stress, which is implicated in ovarian aging and POI. Antioxidant-rich foods include berries, leafy greens, nuts, and fatty fish.
• Melatonin supplementation may help improve ovarian function and reduce oxidative stress in POI. However, more research is needed on optimal dosing.
• Mitochondria-targeted nutrient therapies like alpha-lipoic acid, acetyl-L-carnitine, and coenzyme Q10 may help improve mitochondrial function and reduce oxidative stress in POI.

Exercise

• Regular moderate exercise like walking, cycling, or yoga can help manage symptoms like hot flashes, insomnia, and mood changes associated with estrogen deficiency in POI.
• However, excessive exercise leading to low energy availability should be avoided as it may increase oxidative stress and worsen POI.

Weight management

Maintaining a healthy body mass index (BMI) is important, as being underweight or overweight are both associated with an increased risk of POI.

Stress management

Techniques like meditation, yoga, and counseling may help reduce psychological stress, which is a potential risk factor for POI.

Avoiding smoking

Smoking cessation is recommended as smoking increases oxidative stress and is associated with earlier menopause and POI.

It’s important to note that while lifestyle interventions can help manage symptoms, they may not restore ovarian function or fertility in POI. Hormone replacement therapy remains the primary treatment for managing estrogen deficiency symptoms.

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Recent research has focused on developing innovative treatments to address this condition. Here are some of the cutting-edge treatments on the horizon for women with infertility due to POI.

Stem cell therapy

Stem cell therapy is one of the most promising approaches for treating POI. Various types of stem cells, including mesenchymal stem cells (MSCs) derived from bone marrow, adipose tissue, and umbilical cords, have shown potential in restoring ovarian function. These stem cells can differentiate into ovarian cells and secrete factors that promote tissue repair and regeneration. Studies have demonstrated that MSCs can improve ovarian function and structure in animal models of POI, suggesting their potential for clinical application.

Platelet-rich plasma (PRP) therapy

PRP therapy involves injecting a concentration of a patient’s own platelets into the ovaries. Platelets contain growth factors that can stimulate tissue repair and regeneration. This approach has shown promise in improving ovarian function and increasing the number of viable follicles in women with POI. However, more research is needed to establish its efficacy and safety in more extensive clinical trials.

Mitochondrial replacement therapy

Mitochondrial dysfunction is a key factor in ovarian aging and POI. Mitochondrial replacement therapy aims to replace damaged mitochondria with healthy ones to restore cellular function. This technique involves transferring mitochondria from donor cells into the patient’s oocytes or ovarian cells. Although still in the experimental stage, mitochondrial replacement therapy holds the potential to improve ovarian function and fertility in women with POI.

In vitro activation (IVA)

IVA is a novel technique that activates dormant primordial follicles in the ovaries. This process includes ovarian tissue fragmentation to disrupt the Hippo signaling pathway, followed by culture in an environment that promotes follicle growth. IVA has shown success in animal models and some clinical cases, offering hope for women with POI who have residual follicles.

Cell sheet technology

Cell sheet technology is an innovative method that involves creating a sheet of cells that can be transplanted into the ovaries. This technique has been tested in animal models, showing that cell sheets can improve ovarian function and structure. The cell sheet method may offer a new approach for delivering stem cells or other therapeutic cells to the ovaries, enhancing their survival and integration.

Exosome therapy

Exosomes are small vesicles secreted by cells that contain proteins, lipids, and nucleic acids. They play a role in cell communication and tissue repair. Exosome therapy involves using exosomes derived from stem cells to promote ovarian regeneration. This approach has shown promise in preclinical studies, with exosomes improving ovarian function and reducing apoptosis in ovarian cells.

Biomaterials strategies

Biomaterials can be used to create scaffolds or matrices that support the delivery and retention of therapeutic cells or molecules in the ovaries. These materials can enhance the survival and function of transplanted cells, improving the efficacy of treatments like stem cell therapy and PRP. Research is ongoing to develop biocompatible and biodegradable materials that can be used in clinical applications.

While these cutting-edge treatments offer hope for women with POI, most are still in the experimental stage and require further research to establish their safety and efficacy. The future of POI treatment lies in the continued development and optimization of these innovative approaches to restore ovarian function and improve fertility outcomes for affected women.

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POI is associated with autoimmune diseases in 20 to 30% of cases. The connection lies in the autoimmune mechanism that can lead to ovarian failure and insufficiency.

The ovaries can be targeted by autoantibodies and autoreactive lymphocytes, leading to ovarian dysfunction and depletion of ovarian follicles. Two fundamental autoimmune mechanisms involved include:

• Lymphocytic oophoritis: This is characterized by lymphocytic infiltration of the ovary, leading to follicle destruction and ovarian failure.
• Anti-ovarian antibodies: Autoantibodies can be produced against various ovarian antigens like oocytes, granulosa cells, steroid-producing cells, and gonadotropin receptors. These autoantibodies can impair ovarian function.

POI is frequently associated with other autoimmune disorders like thyroid autoimmunity (Hashimoto’s thyroiditis), Addison’s disease (adrenal insufficiency), autoimmune polyglandular syndromes, and, less commonly, type 1 diabetes or hypoparathyroidism.

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Patients with Hashimoto’s thyroiditis (have a significantly higher risk of developing POI compared to those without autoimmune thyroid disease. 

Women with Hashimoto’s disease have an 89% higher risk of amenorrhea (lack of menstrual periods) compared to those without the disease.

Thyroid autoimmune disease, most commonly Hashimoto’s thyroiditis, is present in 14% to 32.7% of women with POI at initial diagnosis.

Several studies have investigated the relationship between Hashimoto’s thyroiditis and ovarian reserve, which measures the remaining egg supply and fertility potential. One 2022 study found that women of reproductive age with Hashimoto’s thyroiditis had significantly lower levels of anti-Müllerian hormone (AMH) and antral follicle count (AFC), both markers of ovarian reserve. This suggests that Hashimoto’s thyroiditis and other autoimmune thyroid diseases may negatively impact ovarian reserve, potentially increasing the risk of POI.

A nationwide population-based study in Taiwan analyzed data from the National Health Insurance Research Database and found a strong association between thyroid autoimmunity, including Hashimoto’s thyroiditis and Graves’ disease, and an increased risk of POI. Women with Hashimoto’s thyroiditis had an 89% higher risk of amenorrhea (absence of menstrual periods) and a 2.4-fold higher risk of infertility due to ovarian failure compared to women without the condition.

The exact mechanisms underlying the link between Hashimoto’s thyroiditis and POI are not fully understood, but several theories have been proposed.

• Autoimmune attack: Autoimmune thyroid antibodies, such as thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies, may cross-react with ovarian antigens, leading to an autoimmune attack on ovarian tissues and follicle depletion.
• Thyroid hormone imbalance: Hypothyroidism caused by Hashimoto’s thyroiditis can disrupt the delicate hormonal balance required for normal ovarian function, potentially contributing to ovarian dysfunction and POI.
• Genetic predisposition: Some genetic factors may increase the risk of both Hashimoto’s thyroiditis and POI, suggesting a shared underlying susceptibility.

The association between Hashimoto’s thyroiditis and POI has important clinical implications for women’s reproductive health.  Early detection and management of thyroid autoimmunity is essential, as it may help prevent or delay the onset of POI, preserving fertility potential. Additionally, women with Hashimoto’s thyroiditis who are planning to conceive or undergoing fertility treatments may benefit from closer monitoring of their ovarian reserve and tailored treatment approaches.

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The growing body of evidence suggests a significant link between Hashimoto’s thyroiditis and an increased risk of POI. While further research is needed to fully understand the underlying mechanisms, this association highlights the critical importance of screening for thyroid autoimmunity in women with diminished ovarian reserve or POI, and vice versa. Early recognition and appropriate management of these conditions may improve reproductive outcomes and overall health for affected women.

At Paloma Health, we understand the challenges women face in the timely diagnosis and management of Hashimoto’s hypothyroidism. Paloma Health members benefit from an integrative approach that combines the best of conventional medicine with evidence-based natural therapies to address the root causes and provide personalized care. With expert guidance, comprehensive and convenient thyroid function testing, and a treatment plan tailored to your unique needs, you can regain control of your health. Paloma is committed to empowering hypothyroid patients with the knowledge, support, and resources necessary to effectively manage hypothyroidism and improve well-being. Take the first step towards a healthier, more vibrant life by scheduling a consultation with Paloma’s dedicated team of health care providers today.

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