Multiple sclerosis (MS) is an immune-mediated demyelinating inflammatory disease of the central nervous system. This devastating disease commonly manifests as sensory and motor deficits such as numbness, tingling, diplopia, gait disturbance, and imbalance. Relapsing-remitting MS accounts for a majority of cases at commencement of disease and is characterized by definitive episodes with recovery in between1. In these patients, relapses are rarely a cause of severe disability and are used to monitor disease activity2. Given that MS predominantly affects women during child-bearing years, its effect on fertility, pregnancy and ultimately menopause is an integral aspect in care of this unique patient population. It is largely agreed upon that pregnancy is associated with decreased disease activity due to the immunomodulatory effects of estrogen in neurodegenerative and autoimmune inflammatory conditions3–5. There is no definitive data to suggest decreased fertility in women with MS6,7. Interestingly, some studies report decreased ovarian reserve in women with MS and a potential inverse relation to disease activity6,8,9. This is supported by findings of higher follicle stimulating hormone and leutinizing hormone levels in MS patients10. Studies examining the hypothalamus-pituitary-ovary axis have found no significant differences between women with and without MS8. Some attribute infertility due to concomitant thyroid and prolactin derangements which may result in oligomenorrhea or amenorrhea6,10. As women transition into menopausal years, patients with MS have been shown to have improved quality of life, improvement of symptoms and decreased neuronal degeneration with hormone replacement therapy11,12. Furthermore, new data suggests Estriol and Tamoxifen to be promising treatments in women with relapsing-remitting multiple sclerosis13,14.
We present a case report of a 38-year-old G1P0102 Caucasian female who initially presented to a neurology clinic 9 years ago in May of 2010 with disorientation, dizziness, and imbalance. She denied changes in muscle strength, vision, swallowing, bowel, and bladder habits. Her medical history is significant for migraines with aura and secondary amenorrhea for 1 year prior. She has no family history of autoimmune or neurological diseases. She was worked up by a neurology team with multiple magnetic resonance imagings of the brain and a spinal tap and was ultimately diagnosed with relapsing-remitting MS localized to the pituitary stalk (Fig. 1). She was started on disease modifying therapy (interferon beta-1a) soon after diagnosis with stabilization of disease. Ultimately, the patient was referred to Reproductive Endocrinology and Infertility (REI) in December of 2010 for work-up of secondary amenorrhea and primary infertility. Initial laboratories yielded an Estriol of 30.1, leutinizing hormone of 0.4, follicle stimulating hormone of 3.3, and 17-OH progesterone of <40. Prolactin, TSH, insulin-like growth factor-1, ACTH, and cortisol were all within normal limits. Given aforementioned findings, she was diagnosed with primary infertility due to hypothalamic hypogonadism secondary to MS affecting the pituitary stalk given laboratory abnormalities and enhancing lesions on magnetic resonance imaging. She underwent infertility treatment in July 2011 with ovulation induction using human menopausal gonadotropin (225 units of human menopausal gonadotropins) and intrauterine insemination. She conceived triplets and underwent fetal reduction to twins. The patient had an uncomplicated pregnancy and ultimately delivered 2 healthy twin boys in March of 2012. Subsequently, she represented to the REI clinic in March of 2013 with complaints of night sweats and hot flashes. Levonorgestrel/ethinyl estradiol 0.15 mg/30 mcg tablets were initiated for treatment of vasomotor symptoms and bone health given symptomatology. She continued to see REI for management of symptoms and trialed multiple hormone replacement regimens including estradiol 0.0375 mg transdermal patch, conjugated estrogen tablets, venlafaxine, and ethinyl estradiol 50 mcg tablets. The patient’s regimen was optimized in March of 2016 with 0.9 mg of oral conjugated estrogens with progesterone-induced withdrawal bleed every 3 months. She continues to follow-up in the REI clinic for surveillance and is asymptomatic on current regimen.
This case demonstrates an alternative manifestation of MS in a reproductive aged woman. To date, there is no reported case of hypothalamic hypogonadism resulting in secondary amenorrhea and primary infertility. In such a patient with relapsing-remitting multiple sclerosis, after control of disease activity, secondary hypothalamic dysfunction in fertility-seeking women can be treated with ovarian stimulation using gonadotropins. As evidenced by this patient, as patients with MS and hypothalamic deficits transition away from child-bearing years, they may face symptoms of premature menopause which can be adequately alleviated with hormone replacement therapy.
Conflict of interest statement
The authors declare that they have no financial conflict of interest with regard to the content of this report.
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