Names have been changed to protect patient privacy and anonymity.
Background:
Katie, a 15-year-old, had suffered from progressive emotional disturbances ever since her periods began three years before coming to see me. About one week prior to each period, her anxiety levels would rise dramatically and she would become irritable, volatile and have great difficulty sleeping. On the first day of her period, relief would come and she would be back to normal, fearing the next go-round 28 days later.
During freshman year in high school, several events began to distress Katie and socially isolate her. Doctors tended to minimize her problems, telling her this was normal in teenage girls. Eventually, in reaction to her stress and the suffering the PMS would cause, Katie jumped off a bridge in a suicide attempt.
She was then put on progressively higher doses of an SSRI (anti-depressant) – which caused her depression, suicidal impulses and wildness to evolve into a continuous pattern – until she begged to be taken off it. It was at this time that I first met Katie and her parents.
Diagnosis/Treatment:
A neuroendocrine consultation led to a new hypothesis. Due to her family history of both mood disorders and significant PMS and post partum depressions, Katie’s brain was markedly sensitive to the effects that her reproductive hormones – estrogen and progesterone – had on her emotions. She was prescribed natural progesterone, with doses administered at a key time in her cycle.
Results:
In her first menstrual cycle on the progesterone, Katie experienced a dramatic resolution of her anxiety, as well as improved sleep and no severe depression. For the first time in years, she had a positive attitude relating to her menstrual cycle.
This case illustrates a common theme in clinical neuroendocrinology. When adolescent girls start menstruating, the first several cycles can occur without normal ovulation and thus without adequate progesterone levels (but with normal levels of estrogen). This unopposed estrogen state is often highly agitating, commonly in individuals with markers of a “different” brain substrate – for example, a family history of major mood disorders, a distant history of concussion or even left-handedness. Given in the right dose with the right timing, natural progesterone brings dramatic relief to these individuals, as well as those with heightened forms of PMS and even psychotic symptoms.
Background:
During an infertility evaluation 18 years earlier, Jack (now 56) was found to have a low sperm count and elevated levels of prolactin, a hormone that helps women make breast milk but which is also present in men. After a brain MRI, Jack was told he had a pituitary tumor secreting prolactin and was put on a medication called bromocryptine to decrease the prolactin and shrink the tumor.
Over several years, Jack tolerated irritability, anxiety, rapid heart rate and excess sweating, all known side effects of bromocryptine.
Gradually, his dose was lowered to the point where the side effects became tolerable. However, over time, Jack developed a new set of symptoms – fatigue, moodiness, depression and loss of libido.
Labeled as depressed, he was put on sertraline, an antidepressant. The drug made him “very hyper” so he stopped taking it. Afraid his tumor would increase in size, Jack wanted to raise his bromocryptine dose back up, but feared the side effects. Frustrated that his only options seemed to be a life with fatigue, low sex drive and moodiness, or one plagued by irritability, anxiety and excessive sweating, he sought a neuroendocrine consultation.
Diagnosis/Treatment:
Jack’s symptoms (low sex drive, fatigue, moodiness) were typical of low testosterone. When I measured his testosterone levels, they were indeed very low. So were his levels of lutenizing hormone (LH). LH comes from the brain’s pituitary gland and stimulates the testicles to make testosterone. High prolactin levels inhibit this process.
To evaluate the reason for Jack’s high prolactin, I ordered a new MRI brain scan. It showed that Jack had a longstanding condition called empty sella syndrome, which blocks the brain signals that slow down prolactin production. In other words, Jack’s problem was not a pituitary tumor secreting too much prolactin. In fact, he had no tumor at all (and therefore did not require bromocryptine for tumor shrinking).
In light of this discovery, I started Jack on a new regimen where he would apply a topical testosterone gel daily. This would compensate for his low LH levels and normalize his testosterone levels, which were responsible for his fatigue, low libido and depressed mood. As for his mildly elevated prolactin level, he would not need to do anything.
Results:
With high normal testosterone levels achieved, Jack felt energized with a normal libido and positive attitude. For several years now, he has stayed off bromocryptine and antidepressants without any difficulties.
When men develop symptoms of low testosterone – such as loss of sex drive, impotence, fatigue, muscle weakness and depression – blood measurement of testosterone levels is most accurate and should always be paired with the measurement of LH. Many conditions – ranging from head trauma to benign pituitary tumors to epilepsy, chronic stress and more – can lead to low testosterone and LH. The finding of low testosterone must not automatically be attributed to “male menopause,” which would show an associated high LH level and lead to urological investigations. Estrogen levels should also be followed and dealt with accordingly when treating testosterone problems.
Background:
Nancy, 34, had developed Temporal Lobe Epilepsy following a severe streptococcal infection. Three months after finishing treatment for the infection, she began experiencing brief spells characterized by black spots in her vision, stuttering, nausea, dizziness and déjà vu – a feeling of a “wash coming over me,” as she put it. These spells would occur during the third week of her birth control pill regimen.
Interestingly, the amount of estrogen in each pill increased week by week over three weeks before switching to a dummy pill in the fourth week to induce menstruation. Two months after stopping the pills – and one day before her period – she had a generalized tonic clonic seizure, a seizure that affects the entire brain and the type most commonly associated with epilepsy. The next month she had another generalized seizure.
She was eventually put on carbamazapine, an anti-seizure medication. Though she had no more generalized seizures over the next year, she continued to have spells during the premenstrual week of each cycle. Various doctors told her she was having migraines.
Diagnosis/Treatment:
A neuroendocrine consultation led to the diagnosis of catamenial epilepsy. Nancy’s spells, which were actually psychomotor seizures, were occurring during the premenstrual phase of each cycle. At this time, estrogen levels in the blood are high relative to progesterone and progesterone is withdrawing down towards zero. Both of these situations are known to provoke seizures in animal and human studies.
Nancy’s initial spells were brought on by the increasing estrogen levels in her birth control pills. (In addition birth control pills do not have seizure-preventing natural progesterone in them, only synthetic progestins, which do not counteract the effects of estrogen.) When she stopped taking the pill, it took about two months for her natural ovulation to reestablish. When it did, the hormonal forces were so powerful that she had more severe seizures. This establishes that in her natural state of cycling, off birth control pills, she was even more prone to seizures premenstrually – i.e., catamenial epilepsy.
Nancy was prescribed natural progesterone at a robust dose throughout the second half of each menstrual cycle. Carbamazapine levels were not changed initially.
Results:
Over the next 6 menstrual cycles, Nancy had no spells at all. Thereafter, she was able to cut the carbamazapine in half and has remained seizure free for the past year. She will soon discontinue the carbamazapine and go with cyclic progesterone alone.
Based on the specific pattern of seizure occurrence, neuroendocrinologists have defined three types of catamenial epilepsy: 1) perimenstrually; 2) mid-cycle around ovulation; and 3) throughout the second half of each cycle, between ovulation and menstruation. These types are based on dynamic changes in the blood levels of estrogen and progesterone that occur during these specific phases of a woman’s menstrual cycle. Natural progesterone, dosed correctly, stops these catamenial seizures (where standard anticonvulsants cannot) due to the hormone’s interaction with specific seizure-inhibiting receptors in the woman’s brain.
Background:
Christine, 25, had experienced obsessive-compulsive tendencies as a child, with minor effects on her school performance due to low-level anxiety and depression. With puberty, her anxiety and depression increased as did obsessive fears of weight gain. This evolved into paranoid tendencies and racing thoughts concerning her body. She attempted suicide three times throughout high school and college.
Christine had always had irregular menstrual cycles. In recent years, she had experienced the loss of her period and weight gain. She was now on a mood stabilizer, antidepressant and low-dose major tranquilizer, but without much relief.
A reproductive endocrinologist found Christine had an elevated level of DHEAS, a hormone secreted by the adrenal gland above the kidneys. He diagnosed her with polycystic ovarian syndrome, which can affect a woman’s menstrual cycle and appearance, among other things. Due to her psychiatric history, he referred her for a neuroendocrine evaluation to investigate a link.
Diagnosis/Treatment:
Upon hearing Christine’s history – treatment-resistant anxiety, elevated DHEAS, polycystic ovaries – I suspected late onset congenital adrenal hyperplasia, a condition where the adrenal glands have trouble making enough of the hormone cortisol. Cortisol is known as “the stress hormone” for its role in the body’s longer-term response to stress. (Not to be confused with adrenalin, which also comes from the adrenal gland and is the “fight or flight” hormone.)
Tests confirmed a partial blockage in the adrenal pathway that makes cortisol. This explained the build-up of the DHEAS hormone, which is upstream to the blockage. Christine was treated with dexamethasone in a dose just high enough to replace her daily needs of cortisol. This had the effect of turning off her own cortisol pathway and thus lowering her DHEAS levels.
Results:
When she returned two months later, Christine’s DHEAS was normal and her anxieties and obsessive thoughts were well-controlled, without any other changes in her psychiatric medications.
So what was the problem with her elevated DHEAS anyway? Due to the partial blockage in the pathway producing cortisol, Christine’s adrenal system had ramped up its activity in order to maintain an adequate supply of cortisol. As a result, certain hormones upstream from the block, including DHEAS, were accumulating in her bloodstream. These hormones have been referred to as “neuro-active” because they stimulate the brain and exert anxiety-provoking effects. In effect, they were fanning the flames of Christine’s anxiety disorder at these high levels. When they decreased to normal levels, her other medications worked well. We were even able to reduce the number and dose of those she was taking.
Background:
Janet, 40, had been healthy until she suffered a case of viral encephalitis 6 years prior to seeing me. During her hospitalization, her thyroid hormone levels (which control metabolism) were found to be normal. Over the next few months, however, she gained 40 pounds and developed swelling of her hands, feet and face. Her thyroid gland began enlarging and she was treated with thyroid hormone, which had no effect.
Later that year, she gained 23 more pounds, her hair became brittle and her cholesterol level became quite elevated. Tests of her thyroid function were again normal. Doctors progressively raised her dose of thyroid hormone, again without much benefit. A year ago, an endocrinologist evaluated her and stopped all thyroid medication. After this, her hair “stopped growing,” her skin hardened, and she became depressed and forgetful.
She was put on Cytomel, a drug 10 times more potent than regular thyroid hormone. At a dose of 125 mcg per day, she began feeling better, her skin and hair improved, and she lost 20 pounds over two months. Unfortunately, her heart rate increased to 125 beats per minute. Alarmed, she stopped the Cytomel and all of her symptoms returned with a vengeance. Back on 100 mcg of Cytomel – yet still suffering from extreme fatigue, concentration problems, constipation, shortness of breath, excess sweating and weight gain – she was referred to me for an evaluation.
Diagnosis/Treatment:
Tests indicated Janet had normal thyroid function, but she exhibited various symptoms of hypothyroidism (low thyroid function). While regular thyroid hormone treatment had been ineffective in treating these symptoms, Cytomel had reduced them. Unlike regular thyroid hormone, Cytomel had also suppressed her pituitary gland’s thyroid stimulating hormone (TSH) level, indicating her pituitary was sensitive to the more potent thyroid hormone. (TSH levels go down when the pituitary thinks there is enough thyroid hormone in the blood and therefore no need to stimulate production of any more.)
After careful analysis, I suspected partial peripheral resistance to thyroid hormone syndrome. Blood test measurements confirmed that Janet was in a general hypothyroid state, with the exception of her heart, which was racing in a hyperthyroid state (excess thyroid function). She was treated with Cytomel in increasing doses, while a beta-blocker was used to lower her heart rate in consultation with her cardiologist.
Results:
While the benefits from the Cytomel would last for a few weeks or months, it would ultimately lose its effectiveness until the dosage was raised. Janet began feeling better for good on a dose of Cytomel that was nearly 10 times the normal dose for her size and weight – and a maximum dose of the beta-blocker. She returned two years later boasting that she was “svelte” again at 150 pounds. Her mood was good and she was gainfully employed. Her memory, cholesterol, skin and hair were all normal. She has remained on the Cytomel ever since and has had a stable, normal thyroid state.
Of the three known subtypes of thyroid resistance, two are easily detected. The third type – partial peripheral resistance to thyroid hormone syndrome, which Janet had – is harder to recognize. It’s often missed for years while doctors misdiagnose the patient as being depressed or having chronic fatigue. In this case, the pituitary puts out normal amounts of TSH. This leads the thyroid gland to make a normal, but completely ineffectual, amount of thyroid hormone that cannot function in the body. The patient is thus hypothyroid in a clinical sense. Fortunately, the thyroid gland’s resistance can be overridden with sky-high levels of thyroid hormone in the form of Cytomel.
One interesting caveat: different organ systems can become more or less resistant over time, causing certain hyperthyroid symptoms to arise, thus necessitating close observation and response. An example was Janet’s rapid heart rate and sweating on the Cytomel.
Background:
Kathy, 52, reported having severe PMS throughout her life and revealed that birth control pills had made her “crazy” with agitation in her late twenties. For years Kathy had been diagnosed with chronic fatigue syndrome. In her late forties, she had a hysterectomy. Ever since, she had been using Premarin (estrogens) and vaginal estrogen cream to help with night sweats and reduce pain during sex.
While traveling in Central America shortly before coming to see me, she had developed gastroenteritis and needed her gall bladder removed. After that, she had never gotten back on her feet. Over the next six months, she became increasingly confused, depressed, anxious and irritable.
Wondering if her hormones were affecting her emotional state, she came in for an evaluation. In addition to the Premarin, she was on Wellbutrin (an antidepressant) and Oxycontin (a narcotic for pain). Her cognition was mildly impaired with respect to her attention and speed of thinking.
Diagnosis/Treatment:
Kathy’s brain had shown a lifelong sensitivity to the effects of the reproductive hormones estrogen and progesterone. Her history of severe PMS and adverse reaction to birth control pills is evidence of this. Her menopausal transition was bringing predictable hormonal changes and adverse emotional effects.
When she came to me, Kathy was on unopposed estrogen. Because her uterus was gone, there was no risk of uterine cancer from unopposed estrogen and doctors had told her she did not need progesterone. Unfortunately, her brain was feeling the adverse effects of this strategy.
I prescribed a dose of progesterone in a regimen that counterbalanced the estrogen.
Results:
Kathy quickly calmed down with the new treatment. Over a couple weeks, her anxiety and irritability faded and her thinking normalized. A few months later, she had weaned herself off the antidepressant. She has stayed calm and cheerful since.
This case illustrates how natural reproductive hormonal changes throughout life can wreak havoc on moods and emotions, at least for a sizable subset of women. While estrogen elevates mood and enhances thought processes, it can quickly become anxiety-producing and even seizure-provoking under certain circumstances. Progesterone counteracts the estrogen, exerting anti-anxiety and even anti-seizure effects. It also reduces estrogen receptors on brain cells.
With the menopausal transition, estrogen levels decline gradually, which can bring about depressive symptoms and mild cognitive changes in many women. Eventually, as periods start skipping, progesterone levels also decline, which can cause anxiety, irritability and mood swings in these women. Judicious replacement and balancing of estrogen and progesterone – with bioidentical forms of these hormones – is a highly effective and safe way to treat these symptoms.
© 2025 · Alan R. Jacobs, M.D., P.C.