Adult Onset Isolated Hypogonadotropic Hypogonadism- a Cause of Secondary Amenorrhea

A 23-year-old African American female was referred for secondary amenorrhea evaluation. She attained menarche at 12 years and had regular menses. At 18 years, she used OCPs for few months, and used plan B, after which her menses stopped. She had hot flashes and sweating. She was placed on progesterone, but never had withdrawal bleeding. Review of systems was positive for intentional weight loss after her menses stopped, hair loss and nipple discharge. She denied any loss of sensation of smell. She has a PMH of asthma, anxiety and OSA. Family history was not significant for any fertility issues. She smoked cannabis after menses stopped. On physical examination, vitals were stable, BMI of 35 kg/meter2, well-developed secondary sexual characteristics, no thyromegaly, acne or hirsutism. Upon work up, CBC, CMP were normal, Urine pregnancy test was negative, gonadotropins were undetectable (FSH- <0.7mIU/ml, LH- <0.2mIU/ml), anti-mullerian hormone was 3.82ng/ml (WNL), Estradiol was also absent (<15pg/ml), with a low Total testosterone (11ng/dl), TSH was 1.17uIU/ml, Free T4 was 1.1ng/dl, ACTH was 9.58pg/ml, Cortisol was 14.8mcg/dl, and Prolactin was 1.5ng/ml. MRI brain was normal with normal pituitary gland, no focal lesion visualized. Pelvic ultrasound showed ovaries 5.9mL and 4.6mL with multiple follicles present bilaterally. Diagnosis of adult-onset isolated hypogonadotropic hypogonadism (IHH) was made. Patient was started on estradiol patches and progesterone. IHH is a genetic disorder of defective production or action of GnRH. IHH when associated with anosmia is called Kallmann syndrome. It was first described by German American geneticist Joseph Kallmann in 1944. GnRH is a decapeptide, produced in arcuate nucleus and pre-optic nucleus of hypothalamus. GnRH stimulates anterior pituitary to secrete FSH and LH. IHH is caused due to impaired migration of GnRH neurons to brain during embryogenesis. It is inherited as autosomal or X-linked dominant or recessive. Gene mutations associated are ANOS-1, FGFR, PROK-2. It is rare in females. IHH has a broad spectrum of clinical presentation from complete absence of sexual development to partial completion of puberty. It presents with microphallus, cryptorchidism, cleft lip/palate, syndactyly, renal aplasia. In childhood presents with anosmia, hearing deficits, dental agenesis, mirror movements, short stature. During puberty, absent pubertal growth spurt, amenorrhea, lack of virilization, no secondary sexual characteristics, infertility. In partial forms, known as Adult onset or acquired form of IHH, patients have slight testicular growth, thelarche, menarche. Goals of treatment are- pubertal induction, maintenance of sexual maturation and restoration of fertility. In females, pre-puberty only estrogen is given, after puberty both estrogen and progesterone are used, for fertility, pulsatile gonadotropins or GnRH analogues are used.