Luteinizing Hormone Deficiency 

Updated: Nov 04, 2016
Author: Jennifer L Eaton, MD, MSCI, FACOG; Chief Editor: Richard Scott Lucidi, MD, FACOG 

Overview

Background

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. 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.

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]

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.

Epidemiology

Frequency

United States

Hypogonadotropic hypogonadism has an overall incidence of approximately 1:10,000 to 1:86,000 men and women. Two thirds of the time, this 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]

International

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

Mortality/Morbidity

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.

Race

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

Sex

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.

Age

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.

 

 

Presentation

History

Kallmann syndrome presents in males and females with delayed puberty and anosmia. These patients lack secondary sexual characteristics. Female patients also give a history of primary amenorrhea.

In children, idiopathic hypogonadotropic hypogonadism (IHH) can present identical to Kallmann syndrome, but without anosmia. Adult-onset IHH presents in men as sexual dysfunction and infertility and in women as amenorrhea.

Stress-related hypogonadotropic hypogonadism presents in women as amenorrhea. Women who lose 10-15% of normal weight for any reason, including excessive exercise, malnutrition, anorexia nervosa, or bulimia, often experience menstrual irregularities or amenorrhea.[5, 14] Anorexia nervosa presents with weight loss greater than 15% of ideal body weight, behavioral changes (ie, altered self-image), and amenorrhea. Bulimia nervosa typically presents with menstrual irregularities and oligomenorrhea. Patients with anorexia and bulimia may also present with depressive episodes, social withdrawal, and other psychosocial disturbances. Men with hypogonadotropic hypogonadism usually present with a chief complaint of decreased libido and erectile dysfunction.

Pituitary dysfunction in women can result in irregular menses or amenorrhea.[5] 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. Occasionally, patients with pituitary tumors complain of visual changes or headaches. Patients with panhypopituitarism often present with fatigue, hypotension, cold intolerance, or inadequate growth.

Physical

Patients with Kallmann syndrome and IHH fail to develop secondary sex characteristics, eg, facial, body, and pubic hair; musculature; and deeper voice in men and underarm and pubic hair, breasts, and body shape in women. Patients with Kallmann syndrome are also affected by either anosmia or severe hyposmia.

Female athletes in training with amenorrhea caused by hypogonadotropic hypogonadism are noted to have minimal body fat. Patients with anorexia nervosa usually have < 15% ideal body fat. Physical findings in patients suffering from anorexia or bulimia can include lanugo (fine, soft, lightly pigmented hair), dry skin, and/or poor dental enamel from excessive vomiting. Severe cases may result in potential life-threatening gastrointestinal or cardiopulmonary conditions.

Women with prolactinomas present with hyperprolactinemia and, in approximately one third of cases, galactorrhea. Less common symptoms include those related to increased TSH (hyperthyroidism) or GH (acromegaly) levels. Visual field defects resulting from pressure of a pituitary tumor on the optic chiasm are rare. Men or women with panhypopituitarism often have physical findings related to hypothyroidism or adrenal insufficiency.

 

Causes

Kallmann syndrome

  • Genetic

Hypogonadotropic hypogonadism

  • Genetic

  • Idiopathic

  • Prolonged Strenuous Exercise

  • Anorexia Nervosa/Bulimia

  • Starvation

Pituitary dysfunction

  • Pituitary tumors

  • Pituitary Infarction

 

 

DDx

 

Workup

Laboratory Studies

The basic laboratory evaluation for females or males suspected of having luteinizing hormone (LH) deficiency includes serum levels of thyroid-stimulating hormone (TSH), prolactin (PRL), LH, follicle-stimulating hormone (FSH), and estradiol. Low or normal LH and FSH levels in the presence of low estradiol suggest a hypothalamic problem. A pituitary problem 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 determine the presence of a tumor or other abnormality.

MRI of pituitary macroadenoma. MRI of pituitary macroadenoma.

Other Tests

Olfactory testing

When Kallmann syndrome is suspected, olfactory testing can be performed. Screening tests can be performed using vanilla or aromatic oils (eg, wintergreen, cinnamon). Quantitative tests have been developed using either scratch-and-sniff panels or serial dilutions of odorants such as dimethyl sulfide or acetic acid. Perhaps the most widely used clinical olfactory test is the University of Pennsylvania Smell Identification Test (UPSIT) that uses scratch-and-sniff panels.[15]

Screening for eating disorders

Patients suspected of have an eating disorders can be screened for by asking the British SCOFF questions[16] :

  • Do you ever make yourself SICK when you feel uncomfortably full?

  • Do you worry you have lost CONTROL over how much you eat?

  • Have you lost more than 14 pounds (ONE stone's worth of weight) within the last 3 months?

  • Do you believe you are FAT when others say you are too thin?

  • Would you say that FOOD dominates your life?

 

Procedures

Transsphenoidal resection is used to remove pituitary macroadenomas (>1 cm in diameter) that remain symptomatic or increase in size despite medical treatment.

 

Histologic Findings

Pituitary adenomas are rarely malignant. The most common benign adenomas are prolactinomas (70%). Approximately 25% of adenomas do not secrete any hormone (null cell tumors). The remainder secrete TSH, GH, ACTH, and in rare cases, LH and FSH.

 

Treatment

Medical Care

Hypogonadotropic hypogonadism

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

Females with delayed puberty secondary to hypogonadotropic hypogonadism are treated with estrogen to promote development of secondary sexual characteristics. Adult women with hypogonadotropic hypogonadism who desire fertility undergo ovulation induction with injectable gonadotropins. Clomiphene citrate is typically not effective for inducing ovulation in these patients. Women who do not desire pregnancy are treated with estrogen to prevent osteoporosis. Cyclic progestins are added to decrease the risk of endometrial cancer.[17]

Women with hypogonadotropic hypogonadism secondary to anorexia nervosa or exercise can resume normal menses by gaining and maintaining weight equal at least to 15% of ideal body weight. Mild cases of anorexia nervosa may be treated on an outpatient basis under the care of a primary care physician, psychiatrist, psychologist, and/or nutritionist. Severe cases may require hospital admission for aggressive psychiatric rehabilitation and medical management. Mortality associated with anorexia has been reported to be as high as 15%.[18, 19]

Males with delayed puberty secondary to hypogonadotropic hypogonadism are treated with testosterone to promote the development of secondary sexual characteristics. Likewise, adult men with IHH who do not desire fertility are treated with testosterone to restore libido and secondary sexual characteristics.

Adult men with IHH who desire fertility can be treated with a subcutaneous pump that delivers pulses of GnRH. Alternatively, maintenance treatment clomiphene citrate therapy improves both sexual function and sperm production in men with IHH. Clomiphene citrate does not appear to increase testosterone secretion or sperm production in men with Kallmann syndrome.

Pituitary dysfunction

Men and women with LH deficiency secondary to pituitary dysfunction require treatment depending on the presenting symptoms and associated hormonal disorders. Most commonly, these patients have a pituitary adenoma and hyperprolactinemia. Men and women who desire fertility are best treated medically with a dopamine agonist (eg, bromocriptine, cabergoline), which inhibits prolactin secretion. Most patients with macroadenomas (>1 cm in diameter) are treated with a dopamine agonist to decrease the chance of further growth. Women with hyperprolactinemia who do not desire fertility but have amenorrhea are treated with oral contraceptives or cyclic estrogen and progestin as long as they do not have a macroadenoma.[11] Panhypopituitarism can result in life-threatening adrenal crisis (see Addison Disease). Patients with this condition require lifelong treatment with replacement thyroid and adrenal hormones in addition to the medical treatment discussed above.

Surgical Care

Most conditions that result in LH deficiency are not amenable to surgical therapy. One notable exception is the pituitary adenoma. Surgical therapy is required for large pituitary adenomas, those that continue to enlarge despite dopamine agonist treatment or those that impact the visual field irrespective of size. Most commonly, this type of microsurgery is performed using a transsphenoidal approach. This surgery has a risk of panhypopituitarism or persistent nasal leakage of cerebral spinal fluid.

Consultations

Kallmann syndrome

These patients are treated by endocrinologists (pediatric, reproductive, or medical) or urologists, depending on their gender and age. Genetic counseling is important, as this condition is often hereditable.

Hypogonadotropic hypogonadism

Women with this condition are most commonly cared for by reproductive endocrinologists (obstetrician-gynecologists with subspecialty training). Some patients with stress-related hypogonadotropic hypogonadic amenorrhea require psychological therapy as well, particularly in the cases of anorexia nervosa or bulimia, which can be fatal.

Men with hypogonadotropic hypogonadism are usually treated by urologists who specialize in infertility and impotence, since these are common presenting symptoms.

Pituitary dysfunction

Women with isolated hyperprolactinemia or anovulation related to pituitary dysfunction are treated by reproductive endocrinologists. Men with infertility related to pituitary dysfunction are often cared for by urologists who specialize in infertility.

Men or women with panhypopituitarism are cared for by medical endocrinologists. Those with pituitary tumors that are symptomatic (headaches, visual disturbances) or enlarging, despite medical therapy, should be referred to neurosurgeons with special expertise in transsphenoidal surgery.

Diet

No specific dietary recommendations have been made for the conditions associated with LH deficiency.

Activity

No specific activity recommendations have been made for the conditions that cause LH deficiency.

 

Medication

Medication Summary

Medical therapy for patients with luteinizing hormone deficiency varies with respect to cause and if pregnancy is desired.

Androgen

Class Summary

Used in hypogonadism.

Testosterone (Androderm, Androgel, Testim)

Promotes and maintains secondary sex characteristics in males who are androgen deficient.

Estrogen derivative

Class Summary

Used as estrogen replacement therapy.

Estradiol (Estraderm, Estrace, Vivelle, Noven, Climara, Vivelle-Dot, FemPatch)

Restores estrogen levels in girls with hypogonadotropism to concentrations that induce negative feedback at gonadotrophic regulatory centers, which in turn reduces release of gonadotropins from pituitary.

Multiple studies have shown it will prevent bone loss at the spine and hip when started within 10 y of menopause.

Used for the purpose of hormone replacement and induction of puberty. Acts by regulating transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences or hormone-response elements, which enhances transcription of adjacent genes and, in turn, leads to the observed effects.

Ovulation induction agents

Class Summary

These agents induce ovulation.

Follitropin Alfa (Gona-f, Gona-f RFF)

Stimulate gonadal steroid production. Either recombinant or human purified hormone may be used.

Letrozole (Femara)

Oral agent for ovulation induction.

Clomiphene (Clomid, Serophene)

Oral agent for ovulation induction.

Progestational agents

Class Summary

These agents may support the luteal phase of a female who is subfertile in whom inadequate intrinsic luteal phase progesterone is available.

Progesterone intravaginal gel (Progestasert, Crinone Vaginal Gel)

Can be administered PO, vaginally, or IM. All routes of administration are equally effective. Begin treatment 2-3 d after ovulation and continue until 10th wk of pregnancy.

 

Follow-up

Further Outpatient Care

Kallmann syndrome: Patients require lifelong hormonal therapy and specific treatment to achieve fertility.

Hypogonadotropic hypogonadism: Patients with stress-related hypothalamic dysfunction can often regain gonadal function after weight gain or stress reduction. Patients with genetic or idiopathic hypogonadotropic hypogonadism require lifelong hormonal therapy and specific treatment to achieve fertility.

Pituitary dysfunction: Pituitary microadenomas (≤1 cm) often resolve spontaneously. Pituitary macroadenomas (>1 cm) are usually persistent and require at least annual imaging to detect enlargement. Most causes of panhypopituitarism are irreversible and patients require lifelong hormonal therapy and specific treatment to achieve fertility.

 

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.

Prognosis

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

Patient Education

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