Low or low-normal levels of pregnanediol signal less than optimal progesterone. This commonly results in an increase in symptoms occurring in the luteal phase. In the perimenopausal years, progesterone levels tend to fall faster than estrogens, resulting in a relative estrogen dominance. Botanicals or supplemental progesterone can be useful for managing symptoms. Low levels are commonly associated with sleep disturbances, anxiety, stress, and edema.

In postmenopausal women the level of pregnanediol is expected to be much lower than in premenopausal women with optimal luteal ovarian function.

Possible causes of low levels:

- Progesterone is made by the placenta during pregnancy. Pregnanediol is a metabolite of progesterone, which is decreased when placental viability is threatened.

- Ovarian neoplasm: Ovarian epithelial cancers can destroy functional ovarian tissue. Progesterone levels may decrease.

- Amenorrhea, Ovarian hypofunction: Without ovulation, a corpus luteum will not develop. Progesterone will not be secreted, and progesterone and pregnanediol levels will be lower than expected.

Excessive amounts of progesterone in women can result in problems such as dysglycemia (=a broad term that refers to an abnormality in blood sugar stability), alopecia (=hair loss or baldness), acne, and breast tenderness. 

The clinical significance of high levels of progesterone in men is poorly understood. Increased levels of progesterone have been found in states of stress and anxiety in men and women: this may relate to its sedative or stress-countering effects.