Low Progesterone Symptoms Missed by Most Doctors (Depression, and More)

A 53-year-old woman came to my clinic for terrible insomnia and depression. She had already tried all the major antidepressants, was stuck on sleep aids, and felt miserable. Three weeks later she was a whole new woman. But the improvement didn’t come from antidepressants—it came from replacing one key hormone that no other doctor had asked about or tested: progesterone.

What is Progesterone?

Progesterone is one of the major reproductive hormones in women, and to a much lesser extent in men. While it often gets overshadowed by estrogen, progesterone works synergistically with estrogen rather than simply being a “lesser” partner.

Progesterone is derived from cholesterol, and is primarily produced by the ovaries and, to a lesser extent, by the adrenal glands. In pregnancy, the placenta also makes significant progesterone. Surprisingly, your nervous system also produces progesterone, which is why you’ll hear it referred to as a “neurosteroid." Many low progesterone symptoms are related to progesterone's effects in the nervous system.

Progesterone has wide-ranging actions throughout the body:

• In your bones, progesterone promotes bone formation (through osteoblast activation), working together with estrogen.
• In your blood vessels, progesterone helps protect the delicate lining of your blood vessels (endothelial cells), which is important for heart and brain health, especially as you age.
• In your nervous system, progesterone is neuroprotective: it modulates mood, cognition, and may reduce risk of neurodegenerative disease.
• In your immune system, progesterone carries immunomodulatory and anti-inflammatory effects—critical for pregnancy and relevant to chronic conditions.
• And finally, in your reproductive system, progesterone is essential for regulating the menstrual cycle, preparing for and maintaining pregnancy, and reducing the risk of endometrial hyperplasia/cancer.

What are Low Progesterone Symptoms?

Low progesterone impacts bone, cardiovascular, neurological, immune, and reproductive health. Many of the conditions of aging mirror the decline in progesterone.

Some of the symptoms of low progesterone include:

• Breast tenderness, irregular periods, increased appetite, unexplainable aches and pains.
• Increased risk of osteoporosis, as seen in post-menopausal women with low progesterone.
• Increased risk of heart disease, especially after menopause, when progesterone falls.
• In the nervous system: greater likelihood of depression, anxiety, irritability, sleep disturbance, cognitive changes.
• Fatigue in younger and older women can correlate with low progesterone.
• In the immune/ inflammatory domain: low progesterone may lead to increased inflammation, immune dysregulation, or susceptibility to infections.

Progesterone isn’t just a “reproductive” hormone, it intersects with almost every major system in the body

So what causes the dysfunction? Why does progesterone become low or ineffective?

What Causes Low Progesterone Symptoms

Unfortunately, your body is under constant hormonal attack from both the inside and outside. This can disrupt progesterone production and prevent it from attaching to receptors, called "progesterone resistance." Many stressors can disrupt progesterone levels and cause low progesterone symptoms:

• Endocrine-disrupting toxins: Environmental chemicals can interfere with ovarian progesterone production and signaling. This can lead to “progesterone resistance,” meaning the hormone is present but its receptors are dysfunctional.
• Metabolic dysfunction: Conditions like obesity, inflammatory bowel disease, “leaky gut,” and chronic inflammation can impair ovarian progesterone output.
• Stress: Emotional, physical, social, financial stress can all disrupt ovarian function and lowers progesterone production.
• Early‐life and developmental exposures: Childhood malnutrition or early reproductive maturation can have long-term effects on ovarian function and hormone profiles, even in adulthood.
• Genetic factors: Variations in progesterone receptor genes and hormone-metabolism pathways may influence how well progesterone works in your body.

Each of these factors offers an opportunity: if you identify the disruptor, you can intervene—either by modifying the stressor or replacing/bolstering progesterone (or both).

How to Fix Low Progesterone Symptoms

Because progesterone influences so many systems, you might assume that simply replacing it would fix all these issues. It can, but the “how” matters a lot. Here are the key nuances to discuss with your doctor to correct low progesterone symptoms:

• The form of progesterone matters: Bioidentical progesterone (the identical molecule your ovaries produce) behaves differently than synthetic progestins used in many traditional birth-control or hormone-replacement therapies.
  
  • For example, natural progesterone appears to help mood and sleep, whereas many synthetic progestins may worsen mood.
  • Natural progesterone is well known to improve sleep outcomes, especially in post-menopausal women.
• Some women react differently: some women have paradoxical reactions (worse mood or irritability) even with natural progesterone.
• Dose and route are important: oral vs vaginal vs topical routes of progesterone differ in how they affect your body.
  
  • Vaginal suppositories may be preferable in some women with nervous system symptoms (anxiety, irritability, mood swings) if oral progesterone has not worked.
• Balance is key: you must balance progesterone with other hormones (estradiol, testosterone, thyroid, adrenal hormones), metabolic health, sleep, nutrition, gut health, and hormone receptor sensitivity. Many clinical failures attributed to “hormone replacement” really reflect incomplete systems medicine.

Missed Low Progesterone Symptoms and Depression

Progesterone is far more than a “female reproductive hormone.” It carries meaningful effects for mood, sleep, cognition, bone health, cardiovascular resilience, and immune balance. Low levels, or dysfunctional signaling, are frequently overlooked in clinical practice. As I’ve shared with you, the story of my 53-year-old patient was one of transformation when progesterone was addressed.

If you suspect low progesterone symptoms are affecting your insomnia, mood symptoms, unexplained aches, or fatigue, contact Clarus Health today. Speak with a doctor today to learn about our bioidentical hormone replacement program to starting feel your best again.