26 year-old woman with three years of amennorrhea

QUESTION-26 year-old woman presents with three years of amenorrhea. Menarche was at age 13 with initially irregular menses that ultimately normalized by late teens. Her cycles lengthened over a period of one year, around age 22-23 and she has been completely amenorrheic since, without any irregular bleeding. She has had eight negative progesterone withdrawal challenges, but did bleed on OCPs, which she did not tolerate due to side effects.

Patient complains of vaginal dryness, marked reduction in breast volume, and loss of libido. Denies hot flashes. Patient has normal BMI of 21, albeit with some weight fluctuation of approximately 6 kg. She does not do any vigorous exercise and denies mood symptoms. No family history of infertility, irregular menses, hirsutism, male-pattern baldness. Family history of hyper- and hypothyroidism.

Physical exam shows healthy Tanner stage 5 female of normal stature (161 cm) without any notable abnormalities. Normal breast morphology.

Labs obtained at various timepoints over the past three years have shown undetectable and low estradiol (20 to 32) with generous LH at 27.8, FSH 10.3. Repeat showed LH of 15.6, FSH 8.8 with estradiol undetectable throughout. Progesterone 0.14 ng/mL. DHEA-S mildly elevated at 391, repeat was 377. Androstenedione mildly elevated at 346. Total testosterone 41 ng/dL. AMH is elevated to 12 ng/mL. Inhibin B 80 pg/mL. SHBG 57 nmol/L. 17-OH-P normal at 70 ng/dL. TSH normal. AM cortisol 10.5. Normal prolactin. Negative 21-hydroxylase antibodies. Normal 2-hr OGTT.

TVUS showed an endometrial lining of 7 mm and normal ovarian volume showing multiple nondominant follicles.

Patient was given a diagnosis of PCOS. However, it does not seem fitting that her gonadotropins are relatively high given her level of estradiol and symptomatic hypoestrogenemia. POF does not fit with her normal inhibin B and elevated AMH, but could this be a partial gonadotropin resistance? Her timeline seems consistent with cases of resistant ovary syndrome in the literature. Can aromatase deficiency be acquired? Are there any other autoimmune etiologies that might be reasonable to work up? She has been started on HRT for her symptoms. Lilly Chan,MD, MA,

RESPONSE-Because I have not seen a case such as this, I consulted some of my colleagues. My thoughts coincide with theirs, and one told me that he has seen a few similar patients.

Basically it is probable that this patient has PCOS with an overlying hypothalamic component. Thus it would make sense to explore her emotional and social situations, her diet, and her exercise patterns in more detail. It makes sense to provide estrogen in some form with the recognition that she will still have PCOS with any resolution of the hypothalamic disturbance. There is often an overlap between PCOS and functional hypothalamic amenorrhea (FHA). As she recovers her axis, she may or may not develop more features of PCOS as several patients have - some have not (as reported to me).

For now I would just treat her as an FHA patient with lower dose HT. I would stop the estrogen with unscheduled bleeding or after 6 months to a year just to retest the axis.

I always worry that the overlying condition may be a physical abnormality of the hypothalamus and the least expensive form of imaging available to you may well be warranted to rule out an actual lesion. The chances of such a lesion are probably remote.   Robert Rebar, MD