PCOS, hypothalamic amenorrhea present confusing picture for diagnosis, treatment
In May, the Endocrine Society issued a clinical practice guideline for diagnosing and treating functional hypothalamic amenorrhea. A form of chronic anovulation without identifiable organic cause, the condition is often associated with stress, weight loss and excessive exercise.
Functional hypothalamic amenorrhea (FHA) occurs when the hypothalamus slows or stops releasing gonadotropin-releasing hormone, and often affects adolescent girls or women with low body weight, a low percentage of body fat, a very restrictive diet or emotional stress. The condition carries several acute health risks, including delayed puberty, infertility and the long-term health consequences of hypoestrogenism, including decreased bone density and fracture.
FHA affects 1% to 2% of the population, but is more common in athletes who desire a thin body type, such as runners and ballet dancers, according to Michelle Warren, MD, medical director of the Center for Menopause, Hormonal Disorders and Women’s Health in New York, and one of the guideline’s authors.
The guideline notes that FHA may be present in as many as half of patients with mild phenotype polycystic ovary syndrome, a separate condition also marked by menstrual irregularity or amenorrhea and polycystic ovaries. FHA may also be present in women who have a more severe PCOS phenotype with hyperandrogenism, according to Warren, who is also an Endocrine Today Editorial Board Member.
“Both [FHA and PCOS] can cause irregular periods. Although they are two distinct conditions, it is possible to have both of them,” Warren told Endocrine Today. “It creates confusion because with PCOS you have a series of symptoms that are distinct, such as irregular periods with acne, excess hair growth, weight gain and, as a consequence of the irregular periods, trouble conceiving. But it is a distinct syndrome from the FHA, which is a syndrome that generally surfaces with people in an energy deficit.”
A woman with PCOS may not have obesity, acne and hirsutism, and a woman with FHA may not look like she has an eating disorder. Both sets of patients may still menstruate, although their periods are irregular.
Because of the confusing presentation, PCOS in women with FHA can be difficult to diagnose, according to Endocrine Today Editorial Board Member Andrea Dunaif, MD, chief of the division of endocrinology, diabetes and bone disease for the Mount Sinai Health System.
“Based on my clinical experience, I believe a number of women with PCOS develop eating disorders as a way to manage their weight, because of their tendency to gain weight,” Dunaif told Endocrine Today. “Therefore, they can have features of hypothalamic amenorrhea with decreased gonadotropin secretion and low estradiol levels in addition to features of PCOS, such as hyperandrogenism.”
Women and adolescent girls with coexisting PCOS and FHA often present with missed or infrequent menses — the hallmark of both conditions — with PCOS discovered through a hormone profile or ultrasound of the ovaries, according to Dunaif.
“Our guidelines were on FHA, but we brought up PCOS,” Catherine M. Gordon, MD, MSc, chair of the guideline task force and director of the division of adolescent and transition medicine and professor of adolescent medicine and pediatrics at the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, told Endocrine Today. “FHA can mask a diagnosis of PCOS in an adolescent girl in the same way we see it in an adult woman. ... With those two coexisting diagnoses, the presentation is very similar in an adolescent or a woman.”
Similarly, PCOS may mask FHA. In a study of 75 women with WHO group II anovulatory infertility, Mette Petri Lauritsen, MD, PhD, of The Fertility Clinic at Copenhagen University Hospital Rigshospitalet, and colleagues found polycystic ovarian morphology among 52% of the cohort — even when polycystic ovarian morphology was defined as the relatively high cutoff of antral follicle count of greater than 25. Compared with participants who did not have polycystic ovarian morphology, those with the morphology had increased luteinizing hormone, hirsutism and/or elevated total testosterone, free testosterone or androstenedione levels.
“Due to fluctuations in the hypothalamic dysfunction, many women with hypothalamic amenorrhea have levels of gonadotropins within the normal range and are thus classified as WHO group II,” Lauritsen and colleagues wrote. “Although this subgroup should be distinguished from normo-gonadotropic women with a primary ovarian dysfunction, the combination of chronic anovulation and [polycystic ovarian morphology] may imply a diagnosis of PCOS.”
The researchers concluded that “a better distinction between hypothalamic amenorrhea and PCOS could improve treatment strategies for anovulatory infertility.”
Although a large proportion of women with FHA have polycystic ovarian morphology, they do not necessarily have PCOS, Rogerio A. Lobo, MD, professor of obstetrics and gynecology and director of the reproductive endocrinology and infertility fellowship program at Columbia University Medical Center, told Endocrine Today.
“We had always envisioned that it’s basically patients who probably have PCOS who develop FHA,” Lobo said. “It turns out that actually a minority of the women, as they recovered from the amenorrhea and as they resumed their cycles, developed PCOS — the full symptoms, the hyperandrogenism. Our current thinking is that some of these women have a sort of crypto-PCOS. They develop FHA, recover and go back to PCOS. That is relatively rare.”
In a study published in the American Journal of Obstetrics and Gynecology in 2016, Lobo and colleagues found that approximately 10% of women with FHA may have coexisting PCOS. The researchers obtained blood samples from 40 consecutive patients with well-characterized FHA and 28 age-matched controls to measure anti-Müllerian hormone, androgens and other hormones; ultrasound imaging was used to examine the ovaries.
In 32.5% of participants (n = 13), anti-Müllerian hormone was elevated to levels consistent with PCOS (> 4.7 ng/mL), and ovarian volume was greater compared with patients who had FHA without PCOS. Four of those participants had ovarian volume consistent with PCOS ( 10 cc); androgens were in the upper normal range, despite low to normal gonadotropins; and mean total testosterone was significantly greater compared with those with increased anti-Müllerian hormone but normal ovarian size.
“Because no signs or symptoms of this disorder were reported by these women before the appearance of the amenorrhea, it does not seem to be a coincidental relationship,” the researchers wrote. “The possibility that functional hypothalamic amenorrhea favors the appearance of polycystic ovary syndrome or more likely, that a mild (ovulatory) phenotype of polycystic ovary syndrome predisposes to the development of functional hypothalamic amenorrhea should be considered.”
“Our current thinking is that something about FHA predisposes the ovary to become polycystic, and then a subgroup of that actually has PCOS, and a subgroup may mimic PCOS just because of what the ovaries look like,” Lobo said. “The important thing to realize is that a woman who has FHA and is found to have polycystic ovaries is a fairly common finding, and it doesn’t mean she has PCOS.”
Diagnosing PCOS, FHA
With different phenotypes of PCOS and overlap with presentations of FHA — and different long-term health consequences associated with the different conditions — it is important for clinicians to accurately diagnosis these patients, according to Dunaif. Women with PCOS may have increased risks for insulin resistance, metabolic syndrome, cardiovascular disease and diabetes, and those with FHA are at risk for low bone density and future fracture, Dunaif said.
“You have to take a careful history, and you have to look at the endocrine profile carefully to see which syndrome the patient really has,” Warren said.
After excluding other disorders, diagnosis of PCOS can be made based on the presence of two of three conditions: ovulatory dysfunction, polycystic ovarian morphology and hyperandrogenism, according to the 2013 Endocrine Society clinical practice guideline on PCOS. In adolescents, irregular periods and polycystic ovaries may be part of normal development and so hyperandrogenism should also be present for diagnosis of PCOS, according to the guideline.
FHA may be diagnosed if amenorrhea has persisted for longer than 6 months and may be accompanied by weight loss from restrictive eating or an eating disorder. Ovulation can be restored in women with FHA by correcting the causal behavior, likely an energy imbalance from calorie restriction or excessive exercising, according to Gordon.
FHA is diagnosed through elimination and by taking a careful history, Gordon said. Teens and athletes may miss or have irregular periods, but are not considered to have FHA if the situation lasts less than 6 months.
“There is still a wider list on my differential diagnosis that I need to rule out before I get to FHA,” Gordon said. “FHA, manifesting as primary or secondary amenorrhea, is a diagnosis of exclusion. We have to make sure that there’s not an anatomical organic reason for the amenorrhea beyond stress, exercise or not consuming enough calories.”
The clear history part of the diagnosis may be more difficult to elicit, Warren said, because women or teens who are athletes may prefer not to have their periods or may believe that amenorrhea is normal, as their peers also miss their periods.
“They don’t even bring it up as a concern, and sometimes they won’t give us a truthful answer because they’re afraid that if they say, ‘I’m not having periods,’ we’re going to come back and say, ‘You need to run less,’” Warren said.
Early diagnosis of PCOS, ideally during adolescence, is important to prevent the long-term consequences of excess weight and insulin resistance that accompany the condition, Gordon said. The largest chronic health concern in those with FHA is bone loss in women and lack of bone accrual in adolescents.
Some studies have shown that insulin resistance, hyperinsulinemia and greater weight associated with PCOS can protect bone. One study from researchers in Denmark showed that women with PCOS had a decreased risk for fracture compared with their peers who did not have PCOS (OR = 0.79; 95% CI, 0.71-0.8).
However, the hypoestrogenism and lack of proper nutrition often associated with FHA puts bones at risk. In women with PCOS and FHA, “the net effect is negative,” Gordon said. “In other words, any benefits from a high androgen state that a woman with PCOS may have are negated if there is FHA. That estrogen deficiency that is associated with FHA, and other hormonal alterations, leads ultimately to bone loss or, in an adolescent, a lack of bone accrual.”
Women reach their peak bone mass near age 20 to 25 years. Because women with PCOS and FHA are often diagnosed as young women or adolescents, who have yet to achieve their peak bone mass, clinicians should address bone health early, Warren said. Most women with FHA — perhaps two out of three, according to Warren — lose bone as a result of the condition.
The FHA guideline recommends a bone mineral density test for all women and teens with amenorrhea for longer than 6 months. In patients with a low bone density by DXA (BMD z score < –2) and/or a history of frequent fractures, the guideline recommends a short-term trial of transdermal estrogen to restore estrogen stores.
Traditionally, estrogen supplementation in the form of oral contraceptive pills was used to treat FHA in women and adolescents to address low estrogen and protect bones because it was thought that the mechanism was similar to estrogen supplementation improving BMD in postmenopausal women, Gordon said.
“However, many clinical trials have shown that oral contraceptive pills are not protective for bone, due in part to the multiple hormonal alterations secondary to the energy deficit of FHA in addition to estrogen deficiency,” Gordon said. “Oral estrogen also suppressed circulating levels of a signaling factor for osteoblasts — insulin-like growth factor I — which transdermal estrogen does not affect.”
Estrogen replacement alone is not sufficient to address bone loss in these patients, according to Warren. Instead, the guideline recommends addressing the energy imbalance through a multidisciplinary approach.
“Women with FHA have to eat more or exercise less, or in some cases both. Sometimes also cognitive-behavioral therapy or psychotherapy is important to reverse this syndrome,” Warren said.
Both Warren and Gordon use nutritional rehabilitation, decreased exercise and psychological support to address bone health in this population.
Mental health support
Because of the complexity of these two coexisting conditions, it is recommended that a multidisciplinary team, including a medical provider, a nutritionist and a mental health provider, address the concerns.
PCOS symptoms often begin during adolescence when teen girls may be more socially vulnerable, so a mental health provider may be specifically important in this group.
“Since PCOS emerges in adolescence, a time when many young girls are concerned about body image, it’s possible they might feel out of control of their bodies,” Kristen Farrell-Turner, PhD, assistant professor of psychology at Carlos Albizu University, Miami Campus, told Endocrine Today. “One place where they feel like they can gain a little more control is through their diet, and then they may develop an unhealthy relationship with food.”
According to Farrell-Turner, a mental health provider can help both with coping with a PCOS diagnosis and changing behavior in a woman who has developed FHA from an eating disorder.
“In a multidisciplinary team, everyone brings something unique,” she said. “What psychologists bring is sitting down with the patient and going through how beliefs, thoughts and feelings relate to each other and also how they relate to behavior. We can apply any of several different theories that can help patients change behavior.”
In addition, mental health providers have the luxury of more time to spend with individuals than most physicians, Farrell-Turner said.
For women with both PCOS and FHA, it may be especially beneficial for physicians to recommend psychotherapy.
“Though women with PCOS do have an increased risk of depression and anxiety, therapy is not something that is typically recommended,” Dunaif said. “It would be important in a woman with PCOS who had a component of an eating disorder or exercise increase, or who is trying to rigidly manage her weight with these lifestyles changes, so to speak, that therapy have a role.”
In dealing with this complex subgroup of patients, it is important for physicians to treat menses as a vital sign, according to Dunaif.
“It’s not normal for a woman to have irregular or absent menses. Menses should be a vital sign that we, as endocrinologists, should be conveying to the primary care community so that these women are being evaluated,” she said. – by Cassie Homer
- Carmina E, et al. Am J Obstet Gynecol. 2016;doi:10.1016/j.ajog.2015.12.055.
- Carmina E, et al. Gynecol Endocrinol. 2017;doi:10.1080/09513590.2017.1395842.
- Gibson-Helm M, et al. J Clin Endocrinol Metab. 2016;doi:10.1210/jc.2016-2963.
- Gordon CM, et al. J Clin Endocrinol Metab. 2017;doi:10.1210/jc.2017-00131.
- Lauritsen MP, et al. Clin Endocrinol (Oxf). 2015;doi:10.1111/cen.12621.
- Legro RS, et al. J Clin Endocrinol Metab. 2013;doi:10.1210/jc.2013-2350.
- Rubin KH, et al. J Bone Miner Res. 2015;doi:10.1002/jbmr.2737.
- Yüksel O, et al. J Bone Miner Metab. 2001;doi:10.1007/s007740170029.
- For more information:
- Andrea Dunaif, MD, can be reached at Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY 10029; email: email@example.com.
- Kristen Farrell-Turner, PhD, can be reached at Carlos Albizu University, Miami Campus, 2173 NW 99th Ave., Miami, FL 33173; email: firstname.lastname@example.org.
- Catherine M. Gordon, MD, MSc, can be reached at Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., MLC 4000, Cincinnati, OH 45229; email: email@example.com.
- Rogerio Lobo, MD, can be reached at Columbia University Medical Center, 622 W. 168th St., PH 16–64, New York, NY 10032; email: firstname.lastname@example.org.
- Michelle Warren, MD, can be reached at Center for Menopause, Hormonal Disorders and Women’s Health, 134 E. 73rd St., New York, NY 10021; email: email@example.com.
Disclosures: Dunaif, Farrell-Turner, Gordon and Lobo report no relevant financial disclosures. Warren reports she served as a consultant to Yoplait.
Click here to read the , "Are expanding disease definitions unnecessarily labeling women with PCOS?"