Luteinizing Hormone Deficiency

Etiology

LH deficiency can be congenital or acquired but based on the hypothalamic-pituitary-gonadal axis, the causes of LH deficiency can subdivide into hypothalamic and pituitary causes.

Hypothalamic Causes

•  Kallmann syndrome

Kallmann syndrome is a congenital cause of LH deficiency that often presents with hypo or anosmia. It occurs due to genetic mutations that result in the failure of differentiation or migration of gonadotropin-releasing hormone (GnRH) neurons.[2] The neurons form in the olfactory mucosa and migrate to the hypothalamus during embryological development. Some studies suggest these developmental errors result from mutations in the KISS1 gene, which encodes for kisspeptin hormone, a key regulator of the reproductive hormones[3]. Decreased production of GnRH hormone results in reduced production of sex steroids that present as an absence of puberty and secondary sexual characteristics.

• LH beta-subunit mutations 

LH beta-subunit mutations involve inactivating mutations in the beta subunit of LH or LH receptor and result in infertility and amenorrhea due to reduced LH levels required for ovulation. The LH levels may be high as compared to normal, but the mutated hormone lacks functional capacity.[4]

• Idiopathic hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) results from the complete or partial absence of GnRH-induced release of LH and FSH. This condition is relatively rare and can occur in both men and women.[5]

• Stress-related hypogonadotropic hypogonadism

Stress-related hypogonadotropic hypogonadism is caused due to hypothalamic suppression by prolonged strenuous physical exercise and extreme weight loss. These conditions cause an elevation of corticotropin-releasing hormone (CRH), which inhibits pulsatile GnRH release from the hypothalamus, which results in low FSH and LH levels, which present as amenorrhea.[6] Also, endogenous glucocorticoid hypersecretion due to increased CRH and ACTH secretion from physiological or pathological causes of exogenous glucocorticoid therapy inhibits pituitary luteinizing hormone and ovarian estrogen and progesterone secretion.[7]

Pituitary Causes

The pituitary causes are numerous and include pituitary tumors, Sheehan syndrome, hyperprolactinemia,  infection and inflammation, cerebrovascular accidents, and trauma.

• Hyperprolactinemia

Hyperprolactinemia usually results from a prolactin-secreting pituitary tumor (prolactinoma). The high level of prolactin inhibits the secretion of FSH and LH from the anterior pituitary and result in hypogonadism, infertility, and galactorrhea.[8]

• Sheehan syndrome

Sheehan syndrome is caused by massive hemorrhage during childbirth and causes ischemic infarction of the pituitary gland. All the hormones produced by the pituitary are reduced or absent (panhypopituitarism), and the absence of pituitary reproductive hormones (FSH and LH) causes hypogonadotropic hypogonadism.[9]

Epidemiology

The incidence of hypogonadotropic hypogonadism (HH) is between 1 in 10000 to 1 in 86000 in men and women. Almost 66% of the cases are associated with Kallmann syndrome. This syndrome is more common in men. Kallmann syndrome is usually diagnosed in children who present with delayed puberty.

Stress-related hypogonadotropic hypogonadism is common in young women and accounts for 30% of cases of secondary amenorrhea in this age group.

Pituitary tumors are a rare cause and can occur at any age but are usually diagnosed late in adulthood. Idiopathic hypogonadotropic hypogonadism can also occur at any age. 

History and Physical

Kallmann syndrome presents with anosmia or hyposmia with delayed puberty, and lack of secondary sexual characteristics like decreased body and facial hair, lack of deepening of voice [10] and pubic hair, eunuchoid body shape, poor muscle development, small testicles, and small penis in men and lack of breast development and other secondary sexual characteristics in women. Women also give a history of primary amenorrhea. Men can have gynecomastia.

Stress-related hypogonadotropic hypogonadism commonly presents in women of reproductive age who have recently had significant stress or excessive weight loss, such as anorexia nervosa. Factors that cause weight loss and the resulting hypogonadotropic hypogonadism include excessive exercise, psychiatric disorders like anorexia nervosa, and malnutrition.

Idiopathic hypogonadotropic hypogonadism (IHH) in children presents identical to Kallmann syndrome, except for anosmia. Adult-onset IHH presents with sexual dysfunction (loss of libido, erectile dysfunction) in men and amenorrhea in women[11].

Patients with pituitary tumors have varying presentations, but visual disturbance and headache are common. Hyperprolactinemia presents with amenorrhea and galactorrhea in women and impotence, infertility and hypogonadism in men[12][13]. There can be associated galactorrhea in men; however, it is uncommon.

Evaluation

Laboratory tests: The initial evaluation aims to rule out hypothyroidism by measuring serum TSH levels and pregnancy in women. Serum levels of LH, along with FSH and prolactin (PRL), are measured. Pituitary tumors that extend superior to pituitary stalk and suprasellar tumors impair dopamine delivery to the pituitary stalk. They prevent dopamine inhibition of prolactin secretion from lactotrophs and cause hyperprolactinemia.[14] Olfactory testing is used in Kallmann syndrome to diagnose anosmia.

MRI of the head can help to study structural abnormalities in the hypothalamus and pituitary, especially pituitary adenomas.

Treatment / Management

Treatment of LH deficiency depends on the underlying cause, age, and gender, as well as the desired outcome for fertility.

In boys of prepubertal age, androgen (testosterone) replacement therapy will induce puberty and development of secondary sexual characteristics.[15] There is a variety of formulations available in several forms like transdermal patches, gels, IM injections, and oral forms. Testosterone replacement should be started around age 12 to 14 for puberty induction.[16]

In men who have reached puberty, androgen replacement therapy can reverse signs and symptoms of hypogonadism. Testosterone replacement also helps in treating other conditions related to testosterone deficiency like anemia, decreased bone density, muscle atrophy, and alterations in mood/ cognitive abilities.[17] In men who wish to father children, gonadotropin-releasing hormone (GnRH) will assist in achieving fertility. Various gonadotropins, like urinary and recombinant, are available for treatment. The effect of treatment is varied, and it may take up to 2 years of therapy before the initiation of spermatogenesis.[10](B3)

Estrogen therapy is the therapy in prepubertal girls for puberty induction and breast development. Several formulations of estrogen are available and include oral estradiol, oral conjugated estrogen, estrogen gel, and transdermal estrogen patches. The age at which estrogen therapy commences is individualized and incorporates factors such as chronologic age, bone age, absolute height, and psychosocial issues.[18]

In women who desire fertility, ovulation induction occurs with gonadotropins along with estrogen therapy. Ovulation is the result of LH surge during the normal ovulatory cycle and does not occur with regular estrogen replacement therapy. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) are options for this purpose. Women with stress-related hypogonadotropic hypogonadism usually report the resolution of symptoms after the removal of stress. Weight gain also restores hypogonadotropic hypogonadism if it is due to weight loss and decreased fat tissue below a critical level. 

Pituitary disorders are treated based on the etiology and hormone imbalance involved. Hyperprolactinemia caused by pituitary adenomas is treated with dopamine agonists and responds well to medical treatment. Resistant prolactinomas require surgery and close follow up.[19]

Differential Diagnosis

Luteinizing hormone deficiency is a form of secondary hypogonadism and requires differentiation from gonadal disorders that cause primary hypogonadism and other hormonal disorders that affect the pituitary gland and hypothalamus. Following the diagnosis of secondary hypogonadotropic hypogonadism, the clinician must determine the causative disorder.

Differential Diagnosis:

• Primary hypogonadism
• Primary amenorrhea
• Hypogonadism due to thyroid dysfunction
• Luteal phase dysfunction
• Prolactinoma
• Ovarian insufficiency
• Decreased sperm production
• Polycystic ovarian syndrome

Prognosis

Kallmann syndrome and genetic idiopathic hypogonadotropic hypogonadism patients require life long hormone replacement therapy for normal sexual function and fertility. Fertility may not be restored in some cases because the response to hormonal therapy varies from person to person.

Pituitary adenomas may resolve spontaneously if small in size (microadenomas). Microadenomas should have periodic monitoring. Macroadenomas require imaging at least annually to monitor enlargement and may require surgical removal.

Stress-related hypogonadotropic hypogonadism usually resolves after the alleviation of stress and has a good prognosis. Weight-loss related hypogonadotropic hypogonadism, like anorexia nervosa, usually resolves after weight gain.

Complications

Untreated LH deficiency will result in infertility, and if it occurs before puberty, the patient will fail to develop puberty and secondary sexual characteristics. The lack of testosterone will lead to loss of muscle mass, bone density loss, and loss of sex drive in men.