Hypothalamic-Pituitary-Ovarian (HPO) Axis Dysfunction: Lab Testing, Diagnosis, and Treatment

Ovulatory disorders resulting from hypothalamic-pituitary-ovarian (HPO) axis dysfunction account for 25% of infertility diagnoses. There is a broad spectrum of conditions that can lead to HPO dysfunction. To better understand the causes and implications, the WHO divided ovulatory disorders into three groups. While many genetic disorders can result in HPO axis dysfunction, most of the causes are treatable. The key to assessing for ovulatory disorders caused by HPO axis dysfunction is to get thoroughly evaluated by your healthcare provider, so proper steps for determining the root cause can proceed.

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What is The Hypothalamic-Pituitary-Ovarian (HPO) Axis?

The HPO Axis is a synchronized network of communications between the hypothalamus, the pituitary gland, and the ovaries. Hormones and neurotransmitters communicate in a two-way direction between these three organs. Together they regulate reproductive processes and are the primary regulators of the hormones: gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicular stimulating hormone (FSH), estrogen, and progesterone. The end goal of this regulatory system is to carry out all the necessary signaling that creates ovulation.

How Does The Hypothalamic-Pituitary-Ovarian Axis Affect The Woman's Menstrual Cycle?

Feedback loops within the HPO axis coordinate a menstrual cycle. In an optimal functioning menstrual cycle, your period results from Phase 1, ovulation, and Phase 2 completing its jobs. The follicular phase (Phase 1) stimulates ovulation. Ovulation is followed by the luteal phase (Phase 2), which prepares the uterus for potential fertilization. When fertilization does not occur, the uterus sheds the endometrial lining, and menses occurs.

The menstrual cycle is only possible if the hypothalamus, pituitary, and ovaries all work in concert. Release of GnRH from the hypothalamus must occur in order to stimulate the release of LH and FSH from the anterior pituitary gland. FSH is responsible for follicle maturation in the ovaries, which then develops into a mature egg. This process then initiates endometrial thickening and LH release. The LH spike during ovulation allows for a release of a mature egg and a surge of progesterone in the luteal phase. If fertilization does not occur, a period will begin.

All of these steps are necessary for an entire menstrual cycle to be completed. If any of the three organs are not operating properly, signals are not firing, and the network of communications is interrupted. There can also be hormone production complications, causing menstrual cycle dysfunction. Many of these issues can ultimately lead to a lack of ovulation.

What are Ovulatory Disorders?

HPO dysfunction will primarily result in ovulatory complications. Ovulatory disorders manifest as abnormal, irregular, or absent ovulation. This raises a concern because it is a leading cause of infertility. The WHO created a three-group classification for ovulatory disorders resulting from HPO dysfunction:

Group 1- Hypothalamic Pituitary Failure (HPF)

In HPF, there is dysfunction in the communication of the hypothalamus of the brain and the pituitary gland, leading to no GnRH release. Conditions that fit into this group can be congenital, genetic, or acquired through injury or other health matters.

Group 2- Eugonadal Ovulatory Dysfunction

This group encompasses a broad spectrum of conditions that lead to HPO compromise. Within this group are endocrine conditions affecting the pituitary gland, thyroid gland, and complications pertaining to weight.

Group 3-Primary Ovarian Insufficiency or Failure (POI and POF)

These conditions occur when primary ovulatory dysfunction occurs in the ovaries. The etiology of these conditions can be genetic, autoimmune, environmentally induced, or a result of a disease process.

HPO Axis Dysfunction Signs & Symptoms

There are many potential indicators of HPO axis dysfunction. Your signs and symptoms can vary depending on where the disruption is occurring. The main sign of concern is a lack of ovulation, which would lead to infertility. Other common symptoms you may experience are:

• Delayed puberty
• Amenorrhea
• Infertility
• Signs of hypothyroidism
• PCOS symptoms
• Insulin resistance
• Central obesity
• Hyperprolactinemia symptoms
• Symptoms of Turner Syndrome

What Causes HPO-Axis Dysfunction?

Group 1:  Hypothalamic Pituitary Failure (HPF)

The most common HPF condition is Idiopathic hypogonadotropic hypogonadism (IHH), a congenital absence of GnRH. Other causes can be conditions affecting the hypothalamus or pituitary gland independently that affect their ability to send hormonal signals. Some conditions leading to HPF include:

• Kallmann Syndrome
• Specific gene mutations
• Acquired panhypopituitarism (injury to the pituitary gland)
• Intracranial tumors
• Brain radiation therapy
• Langerhans cell histiocytosis
• De Morsier syndrome

Group 2: Eugonadal Ovulatory Dysfunction

Some of the most common causes of eugonadal ovulatory dysfunction include the following conditions:

• PCOS
• Obesity
• Hyperprolactinemia
• Primary hypothyroidism

Group 3: Primary Ovarian Insufficiency or Failure

Some of the most common causes of POI/POF include the following:

• Turner Syndrome (most common cause)
• FMR1 gene mutation that gives rise to Fragile X Syndrome
• Autoimmune thyroiditis
• Autoimmune polyglandular syndromes (APS)
• Environmental toxins
• Cancer treatment
• Menopause

Functional Medicine Labs to Test for Root Cause of HPO-Axis Dysfunction

Dutch Cycling Mapping Test

Evaluating sex hormones, especially those affected by the HPO axis, is a great way to determine if an imbalance is present. DUTCH Cycle Mapping Plus is a dry urine test examining urine samples throughout your menstrual cycle to assess hormone variability. It also includes cortisol testing, which can help with your overall picture and treatment direction.

AMH

Anti-Mullerian Hormone (AMH) is a blood test used to assess egg reserve, AKA egg count. This test is helpful in both evaluating ovarian function and fertility. Investigation for PCOS and infertility often include AMH in diagnostic testing.

Thyroid Panel

Obtaining a complete thyroid panel can rule in or out thyroid involvement. Since ovulatory disorders can be caused by primary hypothyroidism or autoimmune thyroiditis, it’s important to test all thyroid makers including thyroid antibodies.

Conventional Medicine Testing

GnRH stimulation test can determine GnRH levels. This is a test that can be done with guidance from your conventional doctor. It requires an initial blood draw, an IV of GnRH, and multiple blood samples taken over two hours. A final blood sample 24 hours after GnRH treatment will complete the testing. This lab check levels of FSH, LH, and sex hormones to determine GnRH function.

MRI

Imaging will rule out any physical abnormalities that can lead to ovulatory disorder. Conditions like prolactinomas causing hyperprolactinemia, panhypopituitarism, and tumors can all be deciphered on an MRI.

Genetic Testing

A handful of genetic conditions can lead to HPO axis dysfunction. Genetic testing is only routinely done if you are born with a known condition causing ovulatory dysfunction. Ruling out all possible causes through clinical evaluation, blood tests, and imaging would be the first lines of investigation. If no answers result from these tests, consult with your doctor about genetic testing.

Treatment for HPO-Axis Dysfunction

Determining the root cause of HPO-axis dysfunction is key to properly addressing it. From a naturopathic doctor's perspective, it’s important to address the whole person, with extra support to the hypothalamus, pituitary gland, and ovaries. Creating balance in the HPO axis will restore function and vitality for many ovulatory disorder conditions.

Nutrition

Eating quality and whole foods is vital for many areas of health, including supporting this condition. One study evaluated the correlation between lifestyle factors, including diet, of women trying to become pregnant. Over 8 years, the study concluded that those that followed a fertility-based diet rich in fruits, vegetables, plant proteins, and omega-3 fatty acids had more favorable odds of fertility. The study also suggested that this diet can be used in the prevention of infertility due to ovulatory disorder.

Another study examined the calorie intake of female athletes experiencing menstrual irregularities due to HPO axis dysfunction. It revealed that when calories were increased, to take into account expenditure, it can help restore HPO axis function and regulation of their menstrual cycle.

Herbs & Supplements

Vitex (Chasteberry) is a well-researched botanical used for hormone balancing, specifically in supporting progesterone production. Conditions like PCOS, elevated prolactin, and other HPO axis causes of infertility could all potentially benefit from the use of Vitex.

Adaptogenic herbs such as Tribulus can be utilized in reproductive conditions. Literature states that Tribulus can help resensitize receptors of the Hypothalamic-Pituitary-Gonadal axis (another term for the HPO axis) and prevent the need for hormone replacement therapy. Adaptogenic botanicals should be considered when supporting HPO function, as they can support stress. The HPA axis, which is the communication pathway of the stress response, functions synergistically with the HPO axis and can positively or negatively influence it.

Lifestyle changes

Sleep

Getting adequate sleep is important for overall wellness and healing. Hormones function on a circadian rhythm, much like our sleep patterns do. Getting good quality and enough sleep is supportive of sex steroid hormones and gonadotropin secretion, which ultimately supports ovulation.

Acupuncture

The therapeutic intervention of acupuncture follows the tenets of Traditional Chinese Medicine (TCM) and has been utilized for centuries for women's health conditions. Research has shown that acupuncture can help stimulate ovarian function and nourish the uterus.

Summary

The hypothalamic-pituitary-ovarian axis plays a vital role in ovulation and fertility. While there can be many causes, there is limited research on overall HPO axis health treatment. Supporting each organ independently and synergistically with each other is important for the prevention and treatment of ovulatory disorders. Not all conditions resulting in ovulation dysfunction can be cured, such as Turner's Syndrome. But, there are many ways holistic care can improve the symptoms associated with most HPO axis cases. If you or a loved one suffers from delayed puberty, infertility, amenorrhea, or multiple symptoms correlated to HPO imbalance, it would be worthwhile to seek care for appropriate testing and management.