Male acquired hypogonadotropic hypogonadism: diagnosis and treatment

Acquired hypogonadotropic hypogonadism (AHH), contrary to congenital hypogonadotropic hypogonadism (CHH) is characterized by postnatal onset of disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. AHH thus prevents the establishment of gonadotropin secretion at puberty, or its post-pubertal maintenance. Thus, postnatal AHH may prevent the onset of puberty or appear during pubertal development, but it usually emerges after the normal age of puberty. Although pituitary tumors, particularly prolactinoma, are the most common cause, sellar tumors or cyst of the hypothalamus or infundibulum, infiltrative, vascular, iron overload and other disorders may also cause AHH. Pituitary surgery and head trauma or cranial/pituitary radiation therapy are also usual causes of AHH. The clinical manifestations of AHH depend on age of onset, the degree of gonadotropin deficiency, the rapidity of its onset and the association to other pituitary function deficiencies or excess. Men with AHH have less stamina, decreased libido, erectile dysfunction and strength, and a worsened sense of well being leading to degraded quality of life. The physical examination is usually normal if hypogonadism is of recent onset. Diminished facial, body hair and muscle mass, fine facial wrinkles, gynecomastia, and hypotrophic testes are observed in long-standing and complete AHH. Spermatogenesis is impaired and the volume of ejaculate is decreased only when gonadotropins and testosterone levels are very low. Men with AHH may have normal or low serum LH and FSH concentrations, but normal gonadotropin values are inappropriate when associated with low serum testosterone. In the majority of AHH patients, serum inhibin B is "normal". The decrease of this sertolian hormone indicates a long-standing and severe gonadotropin deficiency. Symptoms, usually associated with significant testosterone deficiency in men with AHH, improve with testosterone replacement therapy. Replacement therapy is often simple, using an injectable testosterone ester as first line treatment. Fertility can be restored rather quickly, provided there is no independent primary testicular damage and the partner is fertile.     

A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant

A common cause of micropenis is congenital hypogonadotropic hypogonadism, whether isolated or associated with multiple pituitary hormone deficiencies. The postnatal surge in FSH, LH, and testosterone in the male infant as a consequence of the continued function of the fetal GnRH pulse generator provides a 6-month window of opportunity to establish the diagnosis of hypogonadotropic hypogonadism and alert the clinician to the possibility of its association with multiple pituitary hormone deficiencies. When ACTH or GH deficiency or both deficiencies are present, hypoglycemia and cortisol deficiency can lead to neonatal and infantile death or increased morbidity. Establishing the diagnosis of hypogonadotropic hypogonadism in infancy preempts the uncertainties and delays in distinguishing constitutional delay in puberty from hypogonadotropic hypogonadism. Accordingly, hormone replacement therapy can be initiated at the normal age of pubertal onset. The ontogenesis of infantile testicular function, including the possible significance of the infantile surge in gonadotropins and testosterone, is reviewed. The molecular basis for certain developmental disorders associated with hypogonadotropic hypogonadism and micropenis is considered and the management and treatment of congenital hypopituitarism discussed.     

Hypogonadotropic hypogonadism.

Gonadotropin-releasing hormone (GnRH) and olfactory neurons migrate together from the olfactory placode, and GnRH neurons eventually reside in the hypothalamus. Hypogonadism in male infants may be diagnosed in the first 6 months of life but cannot be diagnosed during childhood until puberty occurs. Patients with low serum testosterone and low serum gonadotropin levels have idiopathic hypogonadotropic hypogonadism (IHH). Mutations in three genes (KAL1, FGFR1, and GNRHR) comprise most of the known genetic causes of IHH. Treatment with testosterone is indicated if fertility is not desired, whereas GnRH or gonadotropin treatment induces spermatogenesis and fertility.     

Hormone substitution in male hypogonadism

Male hypogonadism is characterised by androgen deficiency and infertility. Hypogonadism can be caused by disorders at the hypothalamic or pituitary level (hypogonadotropic forms) or by testicular dysfunction (hypergonadotropic forms). Testosterone substitution is necessary in all hypogonadal patients, because androgen deficiency causes slight anemia, changes in coagulation parameters, decreased bone density, muscle atrophy, regression of sexual function and alterations in mood and cognitive abilities. Androgen replacement comprises injectable forms of testosterone as well as implants, transdermal systems, sublingual, buccal and oral preparations. Transdermal systems provide the pharmacokinetic modality closest to natural diurnal variations in testosterone levels. New injectable forms of testosterone are currently under clinical evaluation (testosterone undecanoate, testosterone buciclate), allowing extended injection intervals. If patients with hypogonadotropic hypogonadism wish to father a child, spermatogenesis can be initiated and maintained by gonadotropin therapy (conventionally in the form of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) or, more recently, purified or recombinant follicle stimulating hormone (FSH)). Apart from this option, patients with disorders at the hypothalamic level can be stimulated with pulsatile gonadotropin-releasing hormone (GnRH). Both treatment modalities have to be administered on average for 7-10 months until pregnancy is achieved. In individual cases, treatment may be necessary for up to 46 months. Testosterone treatment is interrupted for the time of GnRH of gonadotropin therapy, but resumed after cessation of this therapy.     

Melatonin hypersecretion in male patients with adult-onset idiopathic hypogonadotropic hypogonadism.

Increased melatonin secretion observed in male patients with congenital isolated hypogonadotropic hypogonadism and its normalization during testosterone treatment had suggested that melatonin and the reproductive hormones are inter-related. Since these patients have a congenital form of hypogonadism, it is likely that hypermelatoninemia is the consequence of hypogonadism. To further study the relations between the pineal and the reproductive axis in humans, we evaluated melatonin secretion in two men (aged 35 and 50 yrs.) with acquired adult-onset hypogonadotropic hypogonadism. The diagnosis was based on the findings of normal testicular volume, azoospermia, low serum testosterone, normal LH and FSH levels, but apulsatile LH secretion, and intact anterior pituitary hormones secretion, normal findings on skull radiographic imaging, prior sexual maturation and paternity. Melatonin secretion was assessed as urinary 24 h 6-sulphatoxymelatonin excretion (aMT6s) prior to and during the administration of 250 mg testosterone enanthate per month for 4 months. Pretreatment melatonin production was markedly increased in both patients: 427-915 ng/kg/24 h vs. 204+/-81 [mean+/-SD] in 16 age-matched male controls. During testosterone treatment, aMT6s levels were normalized in one patient (range: 81-287 ng/kg/24 h) and remained elevated in the other patient (range: 830-1280 ng/kg/24 h). These data indicate that male patients with acquired GnRH deficiency have increased melatonin secretion. Melatonin hypersecretion in these patients may reflect a functional association.     

Influence of adrenocorticotropin and adrenalectomy on gonadotropin secretion in immature rats

We examined the effects and mechanisms of action of ACTH and ACTH fragments on gonadotropin secretion in immature rats. ACTH administered by daily injection or continuous infusion (osmotic minipumps) attenuated the postcastration rise in serum LH. Pituitary LH concentration was either unchanged or increased in ACTH-treated rats and pituitary sensitivity to gonadotropin-releasing hormone (GnRH) was reduced by ACTH treatment. A fragment of ACTH (ACTH 4-10), which is less steroidogenic, did not alter levels of serum LH, and ACTH did not reduce LH secretion in adrenalectomized castrates. Serum and pituitary concentrations of prolactin were normal in ACTH-treated animals. These studies demonstrate that the suppression of gonadotropin secretion by ACTH is mediated by the adrenal gland. This mechanism causes a decreased pituitary sensitivity to GnRH, but LH synthesis does not appear to be affected. Prolactin does not play a role in this mechanism.     

Hypopituitarism Following Closed Head Injury

We describe four young patients (age 19–34 years) with hypopituitarism following closed head injury. The diagnosis was made by demonstration of low basal pituitary hormone levels and dynamic tests showing low pituitary reserve. The time interval between the injury and diagnosis of hypopituitarism was between three weeks and two months demonstrating the difficulty and complexity of making this diagnosis. Three of our patients (all patients suffering from anterior pituitary hormone deficiency) had ACTH deficiency, a condition which may be life threatening if left undiagnosed; these patients also demonstrated central hypothyroidism. Hypogonadotrophic hypogonadism occurred in three of the patients and was treated with hormonal replacement. Diabetes insipidus was the only insult in one of our patients, accompanied other hormonal deficits in two, and did not appear at all in another patient. Information about skull damage was available for three of the patients, and included skull base and facial bone fractures, probably reflecting the extent of injury necessary to cause hypopituitarism. All patients regained normal lives with adequate hormonal replacement therapy.     

A possible role for reproductive hormones in newborn boys: progressive hypogonadism without the postnatal testosterone peak

Healthy boys have a considerable production of reproductive hormones during the first postnatal months, the biological significance of which is poorly understood. We report on cases of male infants with hypogonadism (hypogonadotropic hypogonadism, n = 1; panhypopituitarism, n = 2) who showed lack of penile growth and involution of the scrotum. In two boys, diagnoses were obtained in early infancy and hormonal measurements at 3-4 months of age showed serum testosterone levels below detection limits in both low inhibin B (37 and 199 pg/mL, respectively; normal range, 193-563 pg/mL) and low to undetectable gonadotropins [LH, undetectable and 0.07 IU/L (normal range, 0.65-2.69 IU/L), respectively; FSH, 0.18 IU/L in both (range, 0.86-2.52 IU/L)]. In a third boy, gonadotropin deficiency was diagnosed at 3 yr of age by undetectable serum levels of FSH and LH both before and after stimulation with GnRH. All cases required hormonal treatment with testosterone, administered as suppositories in daily doses between 1 and 5 mg, which reintroduced male genital development. Our observations suggest that normal phallic and scrotal development in humans is dependent on intact testosterone secretion during early infancy. Additionally, the diagnosis of gonadotropin deficiency may be established in a short-time window postnatally by measurement of spontaneous serum concentrations of reproductive hormones.     

Approach to the male patient with congenital hypogonadotropic hypogonadism

The term "congenital hypogonadotropic hypogonadism" (CHH) refers to a group of disorders featuring complete or partial pubertal failure due to insufficient secretion of the pituitary gonadotropins LH and FSH. Many boys (or their parents) will seek medical consultation because of partial or absent virilization after 14 yr of age. Small testes are very frequent, but height is generally normal. Laboratory diagnosis of hypogonadotropic hypogonadism is relatively simple, with very low circulating total testosterone and low to low-normal gonadotropin and inhibin B levels. This hormone profile rules out a primary testicular disorder. Before diagnosing CHH, however, it is necessary to rule out a pituitary tumor or pituitary infiltration by imaging studies, juvenile hemochromatosis, and a systemic disorder that, by undermining nutritional status, could affect gonadotropin secretion and pubertal development. Anterior pituitary function must be thoroughly investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies and thus to conclude that the hypogonadotropic hypogonadism is isolated. The most likely differential diagnosis before age 18 yr is constitutional delay of puberty. Apart from non-Kallmann syndromic forms, which are often diagnosed during childhood, the two main forms of CHH seen by endocrinologists are Kallmann syndrome, in which CHH is associated with impaired sense of smell, and isolated CHH with normal olfaction. Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry is necessary to determine reliably whether olfaction is normal or partially defective. This step is important before embarking on a search for genetic mutations, which will also be useful for genetic counseling. The choice of a particular hormone replacement therapy protocol aimed at virilizing the patient will depend on age at diagnosis and local practices.     

Isolated combined growth hormone and gonadotrophin deficiency due to hypothalamic dysfunction, associated with insulin resistance

A 47-year-old woman was evaluated for congenital dwarfism, primary amenorrhoea due to hypogonadotrophic hypogonadism, severe hyperlipidaemla with pancreatitis, and overt diabetes mellltus associated with severe Insulin resistance requiring 2.5-3 units of Insulin per kilogram body weight. Chromosomal analysis with trypsin banding was normal and biochemical evaluation revealed low oestrogen levels, inappropriately low gonadotropins, very low IGF-I concentrations and GH concentrations unresponsive to Insulin or l -dopa administration. Prolactin, pituitary-adrenal and pituitary-thyroid axes were normal. Dynamic testing with GnRH and GHRH produced increases in FSH, LH and GH concentrations. A MRI of the brain revealed no discernible hypothalamic abnormalities and a small pituitary. The presence of congenital combined growth hormone and gonadotrophin deficiency on the basis of a suprapltultary defect suggests the existence of common or related pathways regulating GnRH and GHRH synthesis or secretion and may have contributed to the ultimate development of Insulin resistance and hyperlipidaemla.     

A patient of hypogonadotropic hypogonadism accompanied by growth hormone deficiency and decreased bone mineral density who attained normal growth

We present here a rare case of hypopituitarism accompanied by growth hormone (GH) deficiency and hypogonadotropic hypogonadism, in which the patient attained normal height but was of eunuchoid appearance. A 23-year-old man who had not reached puberty was referred to Saitama Medical School for hormonal evaluation. Basal hormonal data and hormone-stimulating tests revealed impaired secretion of GH, gonadotropins and adrenocorticotropic hormone (ACTH). Serum levels of testosterone, estrone, estradiol and estriol were all below the detectable ranges. The patient's plasma ACTH responded to corticotropin releasing hormone, but not to insulin-induced hypoglycemia. Serum GH showed a minimal response to GH-releasing hormone, but was unresponsive to insulin-induced hypoglycemia. Serum luteinizing hormone and follicle stimulating hormone did not respond to luteinizing hormone-releasing hormone. The results were compatible with a diagnosis of hypothalamic hypopituitarism. Magnetic resonance images of the brain showed a small anterior pituitary, an ectopic posterior lobe and transection of the pituitary stalk. Although the patient showed signs of hypopituitarism, he finally attained normal height, possibly because of failed epiphyseal maturation. His bone mineral density was markedly reduced to 0.647 g/cm2 in the lumbar spine; this level was 61.7% of the average level of healthy young males. Our findings were compatible with a recently advocated view that estrogen is important in promoting epiphyseal fusion and in determining bone density in males as well as females.     

Value of gonadotropin-releasing hormone testing in the differential diagnosis of androgen deficiency in elderly men

Elderly men with low testosterone (T) levels are increasingly diagnosed to have partial androgen deficiency of the aging male (PADAM). Frequently, magnetic resonance imaging is performed to exclude pituitary adenoma. The value of GnRH testing to differentiate PADAM from secondary hypogonadism is unknown. Serum levels of T as well as LH and FSH at baseline and after GnRH were evaluated in the following groups: 1) 24 elderly men with low serum T (<11.7 nmol/liter), 2) 25 elderly men with normal serum T levels (>11.7 nmol/liter), 3) 10 men with primary hypogonadism, 4) 24 men with secondary hypogonadism, and 5) 13 healthy young volunteers. In elderly men, T levels were lower (P < 0.001) and gonadotropin levels higher (P = 0.03) compared with younger controls. LH and FSH response to GnRH was higher in elderly men with low T levels (PADAM) compared with elderly men with normal T levels (P = 0.02 and P < 0.001) in the presence of similar basal gonadotropin levels. To differentiate secondary hypogonadism from PADAM with a sensitivity of 100%, a T less than 10 nmol/liter had a specificity of 50%. This specificity was improved to 75% by using a cutoff of less than or equal to 15 mU/liter increase of LH upon GnRH stimulation. Overall, decreased T levels and increased LH levels in elderly men suggest a primary Leydig cell dysfunction. In the subgroup of elderly men with low T levels, an increased LH response to GnRH with normal basal LH levels suggests additional, possibly hypothalamic changes. To exclude secondary hypogonadism in PADAM, diagnostic accuracy can be improved by using GnRH testing.     

Adult-onset idiopathic hypogonadotropic hypogonadism due to isolated pituitary gonadotropin deficiency

A 25-year-old Japanese man with adult-onset idiopathic hypogonadotropic hypogonadism is reported. He had been delivered normally, had normal puberty, and experienced erectile dysfunction at age 24 years. Brain MRI revealed no abnormal findings and endocrinological data supported the diagnosis of isolated gonadotropin deficiency. Although most patients with idiopathic hypogonadotropic hypogonadism have a hypothalamic dysfunction, the lesion in this case may be considered to be in the pituitary since repetitive GnRH loading failed to increase serum LH and FSH.     

Acquired prolactin deficiency in patients with disorders of the hypothalamic-pituitary axis

Acquired PRL deficiency occurs when the anterior pituitary is functionally destroyed, and it usually accompanies other pituitary hormone deficiencies. We retrospectively investigated in an outpatient endocrine clinic of a major tertiary medical center the prevalence and clinical characteristics of acquired PRL deficiency in patients with diseases of the hypothalamic-pituitary axis. The study included 100 consecutive patients, 61 men and 39 women, aged 4-79 yr at diagnosis. Patients were divided by PRL level to normal (>5 ng/ml), mild (3-5 ng/ml), and severe deficiency (<3 ng/ml). Twenty-seven patients (27%) had PRL deficiency, 13 mild deficiency and 14 severe deficiency. Patients with severe PRL deficiency tend to be younger at diagnosis (mean age, 37.5+/-21.8 yr) than patients with normal PRL (46+/-18.5 yr; ns). Underlying diseases including pituitary apoplexy, non-functioning pituitary adenoma, craniopharyngioma, and idiopathic hypogonadotropic hypogonadism were associated with PRL deficiency. The incidence of severe PRL deficiency rose with an increase in the number of other pituitary hormone deficits (ACTH, TSH, gonadotropin, vasopressin), from 0 in patients with no other deficits to 38% in patients with 4 deficits (p=0.006). Patients with severe deficiency had a mean of 3 hormone deficits compared to 1.8 in the other groups (p=0.006). PRL deficiency was significantly associated with TSH, ACTH and GH deficiency. CONCLUSIONS: PRL deficiency is common in patients with hypothalamic-pituitary disorders, especially pituitary apoplexy and craniopharyngioma. Acquired severe PRL deficiency can be considered a marker for extensive pituitary damage and a more severe degree of hypopituitarism.     

Lowering prolactin level in a hyperprolactinemic man: responses of luteinizing hormone, follicle-stimulating hormone, and testosterone

A 25-year-old man with hypogonadotropic hypogonadism and elevated prolactin levels, presumably from a microadenoma of the pituitary gland, was treated with bromocriptine mesylate. After three weeks, the prolactin level had fallen and the gonadotropin levels had shown a substantial rise, reaching supraphysiologic levels by eight weeks, eventually returning to normal by 15 weeks. The serum testosterone level did not rise until after three weeks and reached a maximum by 15 weeks. When the bromocriptine therapy was stopped for one week, all indexes returned to near pretreatment levels. Within two weeks of re-treatment with bromocriptine, the prolactin level had fallen and both testosterone and gonadotropin levels rose. These findings suggest that prolactin may block the secretion of luteinizing-releasing hormone, or may prevent the pituitary gland from responding to it.     

Lack of gonadotropic response to pulsatile gonadotropin-releasing hormone in isolated hypogonadotropic hypogonadism associated to congenital adrenal hypoplasia

Congenital adrenal hypoplasia (AH) is a rare condition, known to be associated with isolated hypogonadotropic hypogonadism (IHH). Three studies have reported attempts to stimulate gonadotropin secretion with pulsatile gonadotropin-releasing hormone (GnRH) in a total of 4 patients presenting such a syndrome, with conflicting results. In the present study, one patient with idiopathic IHH and AH was treated with pulsatile sc GnRH--doses ranging from 2.5 to 10.0 micrograms/pulse, every 90 min--during 8 weeks in an attempt to induce puberty. The prepubertal basal plasma levels of LH, FSH and testosterone, and saliva testosterone levels remained unaltered throughout treatment, at all doses of GnRH tested. The gonadotropin response to an acute iv GnRH administration (0.1 mg) also remained at the prepubertal level after pulsatile GnRH treatment. No circulating anti-GnRH antibodies were detected. The absence of gonadotropic response to exogenous pulsatile GnRH suggests that the IHH of patients with AH is due to an abnormal pituitary function rather than to a lack of endogenous GnRH.     

Hypogonadotropic hypogonadism: hormonal responses to low dose pulsatile administration of gonadotropin-releasing hormone

Patients with isolated gonadotropin deficiency were studied to determine whether pulsatile low dose gonadotropin-releasing hormone (GnRH) could induce the hormonal changes seen during normal puberty. Four male and two female patients with immature responses to a standard GnRH test (2.5 micrograms/kg) were given GnRH (0.025 micrograms/kg) iv every 2 h for 5 days. FSH responses varied between the sexes, and FSH concentrations in males rose continuously to 17.2 +/- 4.7 mIU/ml on day 5. In the females, FSH peaked at 13.8 and 15.8 mIU/ml on days 3-4 and then declined. The males showed increasing and the females decreasing incremental FSH responses to GnRH. LH concentrations and incremental responses to GnRH rose throughout the study in both sexes. Plasma testosterone rose slightly in the males to 0.7 +/- 0.2 ng/ml (P < 0.05), but in females estradiol increased to follicular range concentrations of 128 and 102 pg/ml. Standard GnRh tests on day 6 revealed maturation of gonadotropin responses in all patients. After termination of pulsatile GnRH, four patients were given single low dose GnRH injections on two to seven occasions over a period of 2-32 days. Initial LH responses were 2- to 14-fold greater than those seen on day 5 of pulsatile GnRH, and decreased over the next 3 weeks. FSH responses showed less initial augmentation and declined more slowly. Low dose pulsatile administration of GnRH to patients with isolated gonadotropin deficiency results in changing patterns of hormone secretion similar to those seen during puberty. Exaggerated pituitary sensitivity to GnRH may be present long after a brief period of GnRH stimulation, and may indicate previous rather than current secretion of GnRH.     

Aging of the male reproductive system

Reproductive and sexual physiology, changes in body composition and mental performance in the aging male cannot simply be reduced to presumptive hypogonadism defined by low androgen serum levels or by decreasing levels of growth hormone (GH) and melatonin. Morphological changes in organs at different regulatory levels of hormonal networks governing, for example reproduction, such as diminished hypothalamic pulse generator mass, focal degeneration and loss of Leydig cells in testicular tissue, lead to diminished reserve capacities in production and to loss of coordinated pulsatile release of hypothalamic neuropeptides (e.g. gonadotropin releasing hormone, GnRH) and consequently diminished release of pituitary protein and glycoprotein hormones and testicular steroid hormones. Owing to presumptive alterations in feedback sensitivity, decreased testosterone levels do not necessarily upregulate pituitary LH secretion. Alternatively, increased serum levels of LH and FSH can be observed in old men either because of primary hypogonadism or to decreased hypothalamic opioid tone. In general, endocrine functions are sufficient to maintain fertility in elderly men because, except for sperm motility, quantitative and qualitative functional semen parameters are apparently not affected by age. Nevertheless, reduced endocrine and organic functions might become critical at different levels, with high inter-individual variability, of the hypothalamo/pituitary/gonadal-axis. One of the most intriguing organic manifestations of male aging is benign prostatic hyperplasia (BPH), the pathologic prevalence of which closely matches age. Age-associated changes in the endocrine system and in local networks of epithelial, stromal and luminal factors may play important roles in BPH development.     

Idiopathic hypogonadotropic hypogonadism in men: dependence of the hormone responses to gonadotropin-releasing hormone (GnRH) on the magnitude of the endogenous GnRH secretory defect

Idiopathic isolated gonadotropin deficiency (IGD) is associated with a spectrum of clinical findings as well as variable gonadotropin responses to GnRH. In this study we investigated whether patterns of gonadotropin and testosterone responses to pulsatile GnRH therapy (25 ng/kg, iv, every 2 h for 4 days) were related to the magnitude of the GnRH secretory defect in patients with IGD. Eight men with IGD were studied. Patients with partial IGD (p-IGD) and those who had no evidence of GnRH secretion (n-IGD) were differentiated by the presence or absence of spontaneous LH secretory pulses during 24 h of every 20-min blood sampling. In response to the first GnRH injection, no LH rise occurred in the n-IGD patients, while LH increases in the p-IGD patients were similar to those in normal men. Continuation of GnRH therapy in patients with n-IGD resulted in predominant FSH secretion and absent or minimal augmentation of LH and T secretion. In contrast, predominant LH secretion occurred in the p-IGD patients and resulted in a significant increase in serum testosterone. A bolus dose of GnRH 2 days after the termination of GnRH therapy caused significant augmentation of gonadotropin responses in the n-IGD, while in the p-IGD group, both LH and FSH responses were unchanged compared to those after the first GnRH pulse. These results indicate that IGD is characterized by variable degrees of endogenous GnRH deficiency. Moreover, the hormone responses to GnRH in IGD patients depend on the magnitude of the underlying GnRH secretory defect.     

Androgen deficiency in women with hypopituitarism

Androgen deficiency in men is associated with severe osteopenia, alterations in body composition including an increase in fat mass, and decreased libido. Little is known about the pathophysiology, metabolic consequences, or gender-specific effects of androgen deficiency in women. Acquired hypopituitarism in women is characterized by central hypogonadism and/or hypoadrenalism and therefore may affect critical sources of androgen production in women. We hypothesized that serum androgen levels would be decreased in women with hypopituitarism. We therefore determined serum androgen levels in 55 women with hypopituitarism and 92 controls. This included 4 subsets of hypopituitary women: 1) women less than 50 yr old not receiving estrogen, 2) women less than 50 yr old receiving estrogen, 3) women more than 50 yr old not receiving estrogen, and 4) women more than 50 yr old receiving estrogen. Premenopausal controls with regular menstrual cycles were studied in the early follicular phase, midcycle, and luteal phase during one cycle. All other subjects were studied 3 times during the month at comparable intervals to mimic these 3 time points of the normal menstrual cycle. Serum testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulfate levels were markedly reduced in all 4 groups of women with hypopituitarism compared with controls (P < 0.0001). Moreover, serum testosterone, free testosterone, and androstenedione levels were lower in women with central hypoadrenalism and hypogonadism than in subjects with hypoadrenalism or hypogonadism alone (P < 0.025). Mean DHEAS levels were decreased in hypopituitary women with both hypogonadism and hypoadrenalism compared with those in women with hypogonadism alone (P < 0.0001). These data demonstrate hypoandrogenemia in women with hypopituitarism. The physiological consequences of low androgen levels in this population remain to be determined.