eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility
Luteinizing Hormone Deficiency
Updated: Feb 12, 2008
Introduction
Background
Luteinizing hormone (LH) deficiency is an uncommon condition that 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.
Hypothalamic-Pituitary-Gonadal
Axis 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.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.
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.
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. 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.
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.
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 T 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. 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. 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
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.
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
Luteal phase deficiency (LPD) is a clinical condition in which the amount of progesterone secreted during the luteal phase is insufficient to support implantation and early pregnancy. Whether this condition results from inadequate LH secretion to stimulate progesterone production by the corpus luteum or an inadequate response of the corpus luteum to appropriate LH stimulation is unclear.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.
- 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.
- The incidence of luteal phase deficiency is unknown.
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.
- Luteal phase deficiency is diagnosed only in 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.
- Luteal phase deficiency is found in women of all ages but may be more common in women older than age 35.
Clinical
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. 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. 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.
- Luteal phase deficiency can manifest in women as infertility or recurrent pregnancy loss.
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 anorexic 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.
- Luteal phase deficiency does not manifest with physical findings.
Causes
- Kallmann syndrome
- Genetic
- Hypogonadotropic hypogonadism
- Genetic
- Idiopathic
- Prolonged Strenuous Exercise
- Anorexia Nervosa/Bulimia
- Starvation
- Pituitary dysfunction
- Pituitary tumors
- Pituitary Infarction
- Luteal phase deficiency
- Idiopathic
More on Luteinizing Hormone Deficiency |
 Overview: Luteinizing Hormone Deficiency |
| Differential Diagnoses & Workup: Luteinizing Hormone Deficiency |
| Treatment & Medication: Luteinizing Hormone Deficiency |
| Follow-up: Luteinizing Hormone Deficiency |
| Multimedia: Luteinizing Hormone Deficiency |
| References |
| Next Page » |
References
Cahill DJ, Wardle PG, Harlow CR, Hull MG. Onset of the preovulatory luteinizing hormone surge: diurnal timing and critical follicular prerequisites. Fertil Steril. Jul 1998;70(1):56-9. [Medline].
Fluker M, Fisher S. Anovulation and ovulatory dysfunction. In: Falcone T, Hurd WW. Clinical reproductive medicine and surgery. New York: Elsevier; 2007:277-86.
Kalantaridou SN, Makrigiannakis A, Zoumakis E, Chrousos GP. Stress and the female reproductive system. J Reprod Immunol. Jun 2004;62(1-2):61-8. [Medline].
Lofrano-Porto A, Barra GB, Giacomini LA, Nascimento PP, Latronico AC, Casulari LA. Luteinizing hormone beta mutation and hypogonadism in men and women. N Engl J Med. Aug 30 2007;357(9):897-904. [Medline].
Loret de Mola JR. Amenorrhea. In: Falcone T, Hurd WW, eds. Clinical reproductive medicine and surgery. New York: Elsevier; 2007:233-52.
Mahutte NG, Ouhilal S. Hypothalamic-pituitary-ovarian axis & control of the menstrual cycle. In: Falcone T, Hurd WW, eds. Clinical reproductive medicine and surgery. First ed. New York: Elsevier; 2007:1-16.
McComb JJ, Qian XP, Veldhuis JD, J McGlone J, Norman RL. Neuroendocrine responses to psychological stress in eumenorrheic and oligomenorrheic women. Stress. Mar 2006;9(1):41-51. [Medline].
Patel SS, Bamigboye V. Hyperprolactinaemia. J Obstet Gynaecol. Jul 2007;27(5):455-9. [Medline].
Pritts SD, Susman J. Diagnosis of eating disorders in primary care. Am Fam Physician. Jan 15 2003;67(2):297-304. [Medline].
Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. Aug 30 2007;357(9):863-73. [Medline].
Sehu S, Reddy K, Fleseriu M. Management of pituitary, thyroid and adrenal disorders. In: Falcone T, Hurd WW, eds. Clinical reproductive medicine and surgery. New York: Elsevier; 2007:311-34.
Seidenfeld ME, Rickert VI. Impact of anorexia, bulimia and obesity on the gynecologic health of adolescents. Am Fam Physician. Aug 1 2001;64(3):445-50. [Medline].
Sharma RK. Physiology of Male Gametogenesis. In: Falcone T, Hurd WW, eds. Clinical reproductive medicine and surgery. New York: Elsevier; 2007:73-84.
Solnik JM, Sanfilippo JS. Normal puberty and pubertal disorders. In: Falcone T, Hurd WW, eds. Clinical reproductive medicine and surgery. New York: Elsevier; 2007:157-70.
Walsh BT, Roose SP, Katz JL, Dyrenfurth I, Wright L, Vande Wiele R. Hypothalamic-pituitary-adrenal-cortical activity in anorexia nervosa and bulimia. Psychoneuroendocrinology. 1987;12(2):131-40. [Medline].
Yao MWM, Batchu K. Oogenesis. In: Falcone T, Hurd WW, eds. Clinical reproductive medicine and surgery. New York: Elsevier; 2007:51-72.
Further Reading
Keywords
Kallmann syndrome, hypothalamic suppression, hypogonadotropic hypogonadism, pituitary dysfunction, hyperprolactinemia, luteal phase deficiency, luteinizing hormone deficiency, LH, follicle-stimulating hormone, FSH, thyroid-stimulating hormone, TSH, human chorionic gonadotropin, hCG, gonadotropin-releasing hormone, GnRH, hormone replacement therapy
