Luteinizing Hormone Deficiency

Updated: Sep 30, 2021
  • Author: Jennifer L Eaton, MD, MSCI, FACOG; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Overview

Practice Essentials

An isolated luteinizing hormone (LH) deficiency is an uncommon condition. LH deficiency almost always occurs in conjunction with follicle-stimulating hormone (FSH) deficiency because LH and FSH are secreted by the same pituitary gonadotrope cells. LH deficiency can manifest in females or males as delayed puberty, hypogonadism at any age, or reproductive abnormalities that can be dramatic or subtle. LH and FSH play central roles in the hypothalamic-pituitary-gonadal axis, and, thus, conditions related to LH and FSH deficiency can be caused by pathology of either the hypothalamus or pituitary (see the image below). Careful analysis of the presenting problem, the patient’s overall health, and the hormonal profile is often necessary to determine the cause of LH deficiency and, thus, the most appropriate treatment.

MRI of pituitary macroadenoma. MRI of pituitary macroadenoma.

Signs and symptoms of LH deficiency

Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism lack secondary sex characteristics. Patients with Kallmann syndrome are also affected by either anosmia or severe hyposmia.

Stress-related hypogonadotropic hypogonadism presents in women as amenorrhea.

Pituitary dysfunction in women can result in irregular menses or amenorrhea. In the presence of hyperprolactinemia, approximately one third of women have galactorrhea as well. Men with hyperprolactinemia can present with hypogonadism, impotence, infertility, and/or galactorrhea.

See Presentation for more detail.

Diagnosis of LH deficiency

Laboratory studies

The basic laboratory evaluation for females or males suspected of having LH deficiency includes serum levels of thyroid-stimulating hormone (TSH), prolactin (PRL), LH, FSH, and estradiol. Low or normal LH and FSH levels in the presence of low estradiol suggest a hypothalamic disorder. A pituitary disorder is most commonly associated with elevated PRL levels.

Imaging studies

When hypothalamic or pituitary dysfunction is suspected, the most important imaging study is magnetic resonance imaging (MRI) of the head to detect a tumor or other abnormality.

See Workup for more detail.

Management of LH deficiency

Treatment of hypogonadotropic hypogonadism depends on the gender and age of the patient as well as their desire for current fertility.

Men and women with LH deficiency secondary to pituitary dysfunction require treatment depending on the presenting symptoms and associated hormonal disorders.

See Treatment and Medication for more detail.

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Background

Structure and genetics

LH is a glycoprotein dimer composed of 2 glycosylated noncovalently-linked subunits designated alpha and beta. The alpha subunit is composed of 92 amino acids and is encoded on the long arm of chromosome 6. The beta subunit is 121 amino acids and is encoded on the long arm of chromosome 19.

The alpha subunit of LH is biologically identical to 3 other hormones: FSH, thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG). The beta subunit is unique and determines LH immunologic and biologic activity. The half-life of LH is 20 minutes. The hormone's corresponding receptor is the LH receptor, and mutations of the LH receptor can lead to inactivity or over-activation of LH. [1]

Hypothalamic-pituitary-gonadal

Gonadotropin-releasing hormone (GnRH) is secreted by neurons in the arcuate nucleus of the hypothalamus and released into the pituitary portal circulation. LH and FSH are produced by gonadotrope cells located in the anterior pituitary gland. The gonadotrope cells release LH and FSH in a pulsatile fashion approximately every hour when stimulated by GnRH. Once released into the systemic circulation, both LH and FSH stimulate the gonads of females and males to release steroid hormones. [2]

In the female, LH stimulates the ovary to secrete estradiol, progesterone, and androgens in a cyclic manner and serves as the signal for ovulation. In the first half of the cycle (the follicular phase), LH primarily stimulates theca cells to produce androgens. These androgens are aromatized to estradiol in the granulosa cells of the maturing ovarian follicle under the influence of FSH. At mid cycle, estradiol has a positive feed-back effect on the hypothalamus, which triggers a dramatic spike in the release of LH. This LH surge initiates ovulation and the conversion of the mature follicle into the corpus luteum, which then produces progesterone primarily under the influence of LH.

During the second half of the cycle following ovulation (the luteal phase), LH continues to stimulate the corpus luteum to produce estradiol and progesterone. These steroid hormones act upon the endometrium to make it receptive to embryo implantation. If pregnancy occurs, placental trophoblasts secrete hCG, which stimulates the corpus luteum to continue production of estrogen and progesterone in support of the pregnancy. In the absence of pregnancy, decreasing LH levels cause corpus luteum regression approximately 2 weeks after ovulation. The consequential drop in progesterone results in menstruation. [3]

In the male, both LH and FSH are required for spermatogenesis. LH stimulates Leydig cells to convert cholesterol to testosterone. Testosterone and FSH, in turn, modulate Sertoli cells, which serve as "nurse" cells for spermatogenesis within the lumen of the seminiferous tubules. Clinically, only FSH is used as a marker of testicular dysfunction. [4]

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Pathophysiology

Hypothalamic causes of LH deficiency

Kallmann syndrome

  • Kallmann syndrome was first described by Franz Hosef Kallmann in 1944 and refers to congenital secondary hypogonadism (hypogonadotropic hypogonadism) associated with lack of sense of smell (anosmia). The condition occurs sporadically in 60% of patients, but can be genetically transmitted as an X-linked, autosomal dominant or autosomal recessive condition. [5] This condition affects both females and males who usually present with anosmia and delayed puberty. Laboratory evaluation reveals low LH and FSH levels and normal karyotypes.

  • Females present with primary amenorrhea, and some males present with micropenis. Kallmann syndrome results from the congenital absence of GnRH-producing neurons in the hypothalamus. During embryogenesis, olfactory axonal and GnRH neurons from the olfactory placode fail to migrate to the hypothalamus. In the absence of GnRH, the pituitary gonadotrope cells are not signaled to produce LH and FSH, ultimately leading to lack of sex hormone production by the gonads. [5]

  • Hormone replacement therapy (estrogen for females and testosterone for males) is used to induce sexual maturation and minimize the long-term risk of osteoporosis. When fertility is desired, the treatment consists of either GnRH, given by a subcutaneous pump, or exogenous gonadotropins given by injection. Women with Kallmann syndrome do not ovulate when given clomiphene citrate, which relies on an intact hypothalamic-pituitary-gonadal axis. Likewise, maintenance therapy with clomiphene citrate does not appear to increase testosterone secretion or sperm production in men with Kallmann syndrome.

LH subunit mutation: Mutations of the beta-subunit of LH, leading to hypogonadotropic hypogonadism. [6, 7, 8]

Idiopathic hypogonadotropic hypogonadism

  • Adult onset idiopathic (isolated) hypogonadotropic hypogonadism (IHH) refers to complete or partial absence of GnRH-induced release of LH and FSH in the setting of otherwise normal anterior pituitary anatomy and function. This relatively rare condition can occur in both men and women.

  • In men, estrogen (produced by aromatization of testosterone) has a negative feedback effect on hypothalamic secretion of GnRH and thus inhibits pituitary gonadotropin secretion. It has been hypothesized that some cases of IHH result from an acquired defect of enhanced hypothalamic sensitivity to estrogen-mediated negative feedback since maintenance clomiphene citrate therapy can result in complete normalization of pulsatile gonadotropin secretion, serum testosterone level, and sexual function in men with IHH.

Stress-related hypogonadotropic hypogonadism

  • Hypothalamic suppression can occur in women under physical or metabolic stress. Stress-related hypothalamic suppression is most commonly related to prolonged strenuous physical exercise and extreme weight loss, particularly in the context of eating disorders, such as anorexia nervosa and bulimia. [9] These conditions cause an elevation of corticotropin-releasing hormone (CRH), inhibiting pulsatile GnRH release from the hypothalamus. Suppression of GnRH release in women results in decreased secretion of LH and FSH (ie, hypogonadotropic hypogonadism), manifesting as amenorrhea and hypoestrogenemia. [10] Ongoing hypothalamic suppression can lead to serious consequences such as irreversible osteoporosis and bone fractures in these women.

Pituitary causes of LH deficiency

The anterior pituitary produces a number of important peptide hormones, including LH, FSH, TSH, adrenocorticotropic hormone (ACTH), prolactin (PRL), and growth hormone (GH). LH deficiency can result from a myriad of anterior pituitary dysfunctions including pituitary tumors, inflammation, vascular accidents, and pregnancy-related hemorrhagic shock (Sheehan syndrome).

Hyperprolactinemia is a common hormonal abnormality associated with anterior pituitary dysfunction. Women with high levels of serum PRL (>20-25 ng/mL) often develop galactorrhea, and some develop amenorrhea and hypoestrogenemia. The amenorrhea related to hyperprolactinemia is caused by alterations in the normal release and pulsatility of GnRH as well as subsequent alterations in LH/FSH secretion and the LH surge. [11]

Causes of hyperprolactinemia include pituitary adenomas, hypothyroidism, hypothalamic dysfunction, and chronic renal insufficiency. Medications such as antipsychotics, estrogen, antihypertensives, metoclopramide, and cimetidine can also cause hyperprolactinemia.

Luteal phase deficiency

Historically, the term "luteal phase deficiency (LPD)" described a condition in which progesterone secretion during the luteal phase was insufficient to support implantation and early pregnancy. [7, 8, 12]   There is no reliable test for LPD, and treatment of LPD has not been shown to improve pregnancy outcomes. [13] Therefore, the term has largely been abandoned.

Etiology

The causes of LH deficiency can be summarized as follows:

Kallmann syndrome

  • Genetic

Hypogonadotropic hypogonadism

  • Genetic

  • Idiopathic

  • Prolonged strenuous exercise

  • Anorexia nervosa/bulimia

  • Starvation

Pituitary dysfunction

  • Pituitary tumors

  • Pituitary infarction

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Epidemiology

United States statistics

Hypogonadotropic hypogonadism has an overall incidence of approximately 1:10,000 to 1:86,000 men and women. Two thirds of the time, it is associated with anosmia (ie, Kallmann syndrome).

Stress-related hypogonadotropic hypogonadism accounts for more than 30% of secondary amenorrhea in reproductive-aged women. [5]

Pituitary dysfunction is found in approximately one third of women with secondary amenorrhea. Of these, approximately one third have a pituitary tumor, and one third of those with a tumor have associated galactorrhea. Overall, the prevalence of clinically significant pituitary adenomas is less than 0.01% of the population. [5]

Among childhood cancer survivors who were treated with hypothalamic-pituitary radiotherapy, the estimated prevalence of LH/FSH deficiency is 10.6%. [14]

International statistics

LH deficiency is not unique to any particular country or race.

Race-, sex-, and age-related demographics

LH deficiency occurs in all races. No racial predilection exists.

Kallmann syndrome is 7 times more common in males than in females. Hypogonadotropic hypogonadism occurs in both men and women, but adult onset is more common for women. Pituitary dysfunction occurs in both men and women.

Kallmann syndrome and genetic forms of IHH are usually diagnosed in children with delayed puberty. Adult onset IHH can occur at any age. Stress-related hypogonadotropic hypogonadism is most common in young women. Pituitary adenomas occur at all ages, but the incidence of diagnosis peaks at approximately 40 years of age.

 

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Prognosis

Most causes of LH deficiency are irreversible. However, with appropriate hormone replacement therapy, fertility and a normal life expectancy can be anticipated.

Morbidity/mortality

The primary medical risks of LH deficiency are abnormal development, sexual dysfunction, and infertility. If untreated, resulting hypogonadism also puts patients at risk for medical conditions associated with low testosterone in males and low estrogen in females, including osteoporosis and bone fractures.

Complications

LH deficiency results in infertility and decreased sex hormones if untreated. Complications associated with the secondary lack of estrogen or testosterone can be avoided by replacement hormone therapy. Hypothalamic and pituitary anomalies can result in other hormonal deficiencies (eg, thyroid, adrenal) that can adversely affect health.

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Patient Education

Patients need to be educated about the incidence, pathophysiology, and treatment of their specific condition.

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