Discussion with Danielle Miller, MD on Functional Hypothalamic Amenorrhea

Introduction

Several years ago I wrote a case report on a patient of mine who was diagnosed and successfully treated for functional hypothalamic amenorrhea (FHA). A colleague of mine who specializes in fertility wellness helped me a great deal with this case. She and I recently got together on Zoom to discuss details of the case. We thought a conversation about FHA which would appeal to those both with and without medical training was in order. I hope you enjoy the video and the show notes.

Dr. Danielle Miller’s Bio

Dr. Miller is from Boston, MA where she attended Brandeis University to study premedical sciences and obtain degrees in Spanish Literature and Women’s Studies. Later, she moved to New York City where she spent a year working as an advocate for victims of domestic violence. She then moved to Philadelphia where she earned an MD from Drexel University School of Medicine and studied restorative reproductive medicine, an approach that focuses on healing the underlying causes of fertility problems. After graduating, she trained in family medicine in Lancaster, PA where she pursued further training in restorative reproductive medicine.

Through her years in medical training and since, Dr. Miller has taken many opportunities to learn additional approaches towards healing a variety of women’s health and fertility problems. After several years working as an employee, Dr. Miller created and opened her own direct care practice. It’s called Luz Medicine and it’s located in Lancaster, Pennsylvania.

Since the fall of 2020, Luz has been a medical home to patients looking for a true partnership with their doctor. Luz Medicine serves general family medicine patients, children, adults, and geriatrics through the direct primary care model.

Dr. Miller and her team also help treat those with reproductive health concerns in their fertility wellness care. Through her career, patients have often sought care with Dr. Miller for concerns such as abnormal or missing periods, miscarriage, and infertility. She highly values listening as an essential element of her medical care and credits her patients with helping her learn to address their reproductive concerns. Dr. Miller calls the work she does with women and couples “fertility wellness” since it is born out of the mutual desire of both patient and doctor to help the patient’s body restore normal fertility function so they can achieve their health and reproductive goals.

Finally, besides her love of learning and working with patients, Dr. Miller also enjoys occasional opportunities to teach students, colleagues, and the public about her favorite topics in medicine.

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• Dr. Miller’s Practice: Luz Medicine

00:00 Introduction

03:45 Case Presentation

The case has been written up in great detail on my website, but here is a short presentation:

A 27-year-old female presented to me in 2019 with three years of progressive symptoms which began with the loss of her menstrual period. This was followed by gradually worsening generalized fatigue, fragmented and restless sleep, and decreased exercise motivation and tolerance. Several other signs and symptoms appeared intermittently: headaches, light-headedness, palpitations, dry skin, and muscle aches and cramps. She had menarche at age 14, regular menses through college at which time she weighed 154 pounds at 5’7‘’. At the time of presentation she was 149 lbs.

06:00 Danielle’s approach to the clinical history of amenorrhea

Danielle spends up to an hour discussing the patient’s menstrual history including onset and pattern throughout life up until the time the menstrual period ceased to occur. She also discusses the patient’s nutrition, body composition, and other factors such as sleep stress, and exercise volume and intensity.

08:00 The differential diagnosis of amenorrhea

There are a great many reasons that a woman can lose her menstrual period including anatomic, endocrine, neurologic, and malignant. Here is a breakdown from my longer article on the topic:

1. External – caused by external factors such as starvation, exercise, or stress.
2. Central – caused by damage or dysfunction of the central controllers – the hypothalamus or pituitary, such as a tumor of the pituitary gland.
3. Peripheral – caused by a problem with the peripheral glands or tissues like the thyroid, adrenal glands, or pancreas – such as hypothyroidism or congenital adrenal hyperplasia.
4. Gonadal – caused by a problem with the ovaries such as polycystic ovary syndrome or hyperandrogenism1.
5. Genital – caused by a problem with the genital tract such as scarring of the uterus or an obstruction of the outflow tract.

09:00 Primary vs. secondary amenorrhea

The causes of amenorrhea are generally divided into primary and secondary causes. Primary amenorrhea refers to a scenario in which a woman has never had a menstrual period. This has causes that are outside the scope of our discussion, but which are discussed in my article.

Secondary amenorrhea refers to a scenario in which a woman has had a menstrual period, and thus has proved that she was capable anatomically and hormonally of generating a normal menstrual period, but then for one reason or another has lost that ability.

10:25 Case details: caloric restriction, exercise volume and intensity, body composition

This patient was restricting carbohydrate intake to 100 grams daily and limiting calories to 2000 kcal daily. At the time of presentation, she was training in Crossfit at a high level almost daily, and performed other exercise on top of this. Her BMI was 22, but this doesn’t adequately represent the patient’s leanness and muscularity. Both weight and BMI are crude measures and cannot fully describe a patient’s body composition. In this case, we obtained a DXA scan to more adequately quantify the patient’s body composition. This patient had a DXA demonstrating 17% body-fat, which is quite low for a woman of child-bearing age.

12:00 Danielle’s thoughts on the clinical history

Danielle discusses the case. She mentions how important it is to understand a patient’s body composition at different times in her menstrual history.

14:10 Danielle thinks of FHA and polycystic ovarian syndrome as two opposite ends of a spectrum

PCOS is a hyperstimulated, hyperandrogenic, high-energy state in which the patient often shows signs of metabolic syndrome. The elevated LH levels cause over-stimulation of the ovaries which can cause the development of excess follicles which may be described as polycystic on ultrasound. Ovaries will usually have more than 10 follicles (cysts) and the ovarian volume may be elevated > 10 or 15 ccs.

In many ways, FHA is the opposite. FHA is due to hypostimulation of the gonadal axis with low androgens and estrogens, is usually associated with low-energy consumption, high-stress, and leanness. LH and FSH are low in absolute terms and also lack their typical pulsatility. The reproductive organs are hypostimulated. The ovaries may have fewer than 5 follicles and the ovarian volume may be similar to a woman who is pre-menarchal or post-menopausal. That is, they may be very small, < 5 ccs.

18:40 The differential diagnosis of secondary amenorrhea

You have to consider FHA, PCOS, hyperprolactinemia, pregnancy, medications and several additional diagnoses. Of these, FHA and PCOS are far and away the most common, but other diagnoses that pose a danger must be considered and ruled out. FHA is considered to be a diagnosis of exclusion.

20:35 How Danielle differentiates FHA from PCOS

As mentioned above, FHA is an energy-poor hypostimulated state whereas PCOS generally occurs in a metabolic state of energy surplus and hyperstimulation.

The primary methods of differentiating the two are clinical history, hormone levels, and ultrasound findings.

Even though you can think of these two entities as existing on a spectrum, it’s actually possible to have both at the same time. That is, for instance, an individual could have underlying PCOS with superimposed FHA.

Source

22:10 Pelvic ultrasound findings in FHA vs. PCOS

In FHA, the ovaries will usually be small, the endometrial lining will be thin. There should be a normal or less than normal number of follicles. In PCOS, the ovaries are likely to be normal or large and may have more than 10 follicles. In some cases, these can be enlarged. The ovaries should have normal or elevated volume, which is greater than 10 or 15 ccs.

29:00 Diagnostic thresholds and what is “normal?”

Different references cite various normal thresholds for ovarian follicle count, ovarian volume, and hormone levels.

Danielle considers roughly 5–10 follicles and an ovarian volume of 5–10 ccs to be normal for a healthy woman of child-bearing age without menstrual dysfunction.

Some resources state that ovaries up to 15 ccs are normal and that up to 15 follicles is normal. We discuss the idea that PCOS is common. As many as 1 in 9 women of child bearing age have PCOS. Normal values come from population averages. If many women have clinical or sub-clinical PCOS, it could be that these women falsely elevate our expectations for “normal” ovarian volume and follicle counts.

30:30 Endometrial thickness and tubal thickness

FHA – normal or thin lining depending on the duration of the condition.

PCOS – thick echogenic lining.

For healthcare professionals attempting to interpret pelvic ultrasound findings for the purposes of diagnosing a cause of amenorrhea, I highly recommend reading “A systematic approach to imaging the pelvis in amenorrhea.”

34:10 Laboratory findings in FHA vs. PCOS

In FHA, LH and FSH will both be low, and they will usually be nearly equal to one another. E2 is low, < 50 pg/ml, prolactin, TSH, and T4 will be normal or low, DHEA-S is normal, and T is low normal. In PCOS, LH is greater than FSH. LH is usually less than 15 IU/L and FSH < 10 IU/L. E2 is less than 50 pg/mL, but will usually be higher than in FHA. For instance, in my patient, initial E2 was 19.4 pg/mL which increased to 90.1 pg/mL when the patient’s menstrual period returned.

In PCOS, it’s common to have an elevated fasting insulin, fasting glucose, and an elevated A1C as well as dyslipidemia. PCOS is associated with an energy surplus and metabolic syndrome.

In FHA, fasting insulin and glucose are typically normal or low. In my patient, her fasting insulin was 5 mIU/ml and her fasting glucose was 90 mg/dl. Her Hgba1c was 4.9%.

44:10 Proper timing of measuring hormones in a patient with amenorrhea

How does one know when to measure hormones when a patient has had long-standing amenorrhea. Ideally, you might want to wait for a mid-cycle measurement. In some cases, Danielle has waited for a patient to have a menstrual period, but it never came. This only delayed the workup and diagnosis. Danielle recommends just checking the hormones at the time of the patient’s presentation regardless of where in the cycle she might be. Trying to time this in a patient with amenorrhea is very difficult. It’s best not to waste time. We can always measure labs again later if the patient has a menstrual period.

47:00 Danielle’s female baseline lab panel

It includes: prolactin, thyroid studies including antibodies, androgens, LH, FSH, estradiol, and progesterone.

48:30 Androgens in PCOS

Androgens like DHEA and T are typically high-normal or elevated in PCOS.

49:00 How stress contributes to the pathophysiology and treatment of FHA

FHA is not only caused by nutritional restriction and excessive exercise, but also by other physiologic and psychological stressors. It’s common for women with FHA to have a great deal of psychological stress either due to the amenorrhea itself, or other factors in life. Sleep deprivation is also a common contributory cause and effect of FHA. In essence, the hypothalamus is responsible for managing metabolic resources. If there is a great deal of stress on an individual, the hypothalamus can conserve resources by shutting off reproductive capability, which requires a great deal of internal and external resources. In some cases, psychological stress alone can cause amenorrhea, which, evolutionarily, makes some sense.

In addition, the treatment of FHA often involves increasing nutritional intake, decreasing exercise, gaining weight, sleeping more, dealing with psychological stressors, and other stressful and difficult changes. My patient made many changes in a relatively short period of time. She had a great deal of support to get her through these changes. This is an essential aspect of the treatment of FHA. All professional guidelines recommend multimodal approaches, especially for athletes.