Treatment of hypopituitarism

INTRODUCTION — Treatment of patients with hypopituitarism is the sum of the treatments of each of the individual pituitary hormonal deficiencies detected in a patient with pituitary or hypothalamic disease. The treatments of corticotropin (ACTH), thyroid-stimulating hormone (TSH), and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiencies are in many ways the same as the treatments of primary deficiencies of the respective target glands, but in other ways they differ. Both the similarities and differences will be highlighted below. Treatment of growth hormone (GH) deficiency is unique to hypopituitarism.

The specifics of therapy for hypopituitarism will be reviewed here. The causes, clinical manifestations, and diagnosis of hypopituitarism, as well as GH deficiency in adults and the management of individual hormone deficiencies, are reviewed in more detail elsewhere. (See "Causes of hypopituitarism" and "Clinical manifestations of hypopituitarism" and "Diagnostic testing for hypopituitarism" and "Growth hormone deficiency in adults".)

ACTH DEFICIENCY — The primary consequence of lack of corticotropin (ACTH) is cortisol deficiency. As a result, treatment consists of the administration of hydrocortisone in an amount and timing to mimic the normal pattern of cortisol secretion. Because there is no test to assess the adequacy of the replacement, the optimal doses are not known. Most authorities recommend replacement with hydrocortisone because that is the hormone the adrenal glands make normally (hydrocortisone and cortisol are different names for the same chemical structure).

Preparation and dose — Most authorities recommend hydrocortisone doses of 15 to 25 mg/day [1,2] because those doses are similar to daily production rates [3]. Patients who are more severely deficient or weigh more tend to need doses at the upper end of this range and vice versa. Some patients, however, need even larger doses to avoid severely symptomatic adrenal insufficiency, and others can get by on smaller amounts. (See "Treatment of adrenal insufficiency in adults", section on 'Initial dosing'.)

Although dividing the total daily dose into two or even three doses (with the largest dose on arising in the morning) makes sense physiologically, many patients cannot remember to take doses in the middle of the day. For them, taking the entire dose in the morning is preferable to missing doses. Most patients feel well while taking the entire dose on arising.

A modified-release formulation of hydrocortisone is available in some countries, but not in the United States. In one study, 15 to 20 mg of this preparation given at 11 PM and 10 mg at 7 AM gave a pharmacokinetic profile similar to normal adrenal cortisol secretion [4].

Whatever the preparation and dose, the patient should be instructed in the need for larger doses in times of illness, surgery, procedures, and other physical stresses. (See "Treatment of adrenal insufficiency in adults", section on 'Initial dosing'.)

An inadequate dose may result in persistence (or recurrence) of the symptoms of cortisol deficiency, while an excessive dose can lead to symptoms of cortisol excess and bone loss. Small deviations from the optimal dose are usually not detected clinically. (See "Epidemiology and clinical manifestations of Cushing syndrome".)

Assessment of dose adequacy — Unlike replacement of other pituitary-dependent hormones, no tests exist to assess objectively the adequacy of the replacement of cortisol, as illustrated by the following:

●Plasma ACTH measurements cannot be used, because the values are low or normal before treatment.

●Serum cortisol values vary from patient to patient and in relation to the timing of the hydrocortisone dose. This was illustrated in a study of 46 patients with adrenal insufficiency, 23 of whom had a secondary cause, stably treated with cortisone acetate. Clinical status was assessed by a questionnaire, and serum cortisol concentrations were measured for up to eight hours after a single 25 mg dose [5]. In the 33 patients considered clinically "well replaced," the serum cortisol concentrations not only fluctuated from a mean maximum of approximately 21 mcg/dL at two hours after the dose to 7 mcg/dL six hours after the dose, but varied among individuals from <14 to >28 mcg/dL at two hours and from virtually undetectable to >14 mcg/dL at six hours. (See "Diagnosis of adrenal insufficiency in adults".)

●Salivary cortisol values also fluctuate widely and do not correlate with plasma values after oral administration. In a study of 27 patients with adrenal insufficiency, 18 of whom had a secondary cause and who were stably treated with hydrocortisone, plasma and salivary cortisol were measured for eight hours after a single 20 mg dose [6]. The plasma concentration fluctuated widely among patients, as shown by a fivefold variation in area under the curve. The correlation between plasma and salivary cortisol was poor.

●Urinary cortisol values are also unreliable for the assessment of adequacy of hydrocortisone dose.

●Consequently, the adequacy of the replacement dose must be judged by much cruder clinical criteria, such as Cushingoid features when the dose is quite excessive and symptoms of adrenal insufficiency when the dose is quite insufficient.

●Clinical effects of the modified-release formulation of hydrocortisone described above [4] were assessed in a group of 89 patients with adrenal insufficiency, 43 assigned to continue taking their standard dose of hydrocortisone two to three times a day and 46 assigned to take the same total amount but given as a single dose of the modified-release preparation on awakening [7]. Those treated with the modified-release formulation, after 24 weeks, weighed less (-2.1 kg versus 1.9 kg) and had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the group who received the total divided into two to three doses.

Subjective health status — As a possible consequence of the lack of objective measurements of the adequacy of the replacement dose of glucocorticoid, patients with adrenal insufficiency have impaired self-reported health status by standard questionnaires. This was illustrated in a study of 210 patients with adrenal insufficiency, 78 of whom had a secondary cause. Scores on validated self-assessment questionnaires (SF-36, Geissen Complaint List, and Hospital Anxiety and Depression Scale) were significantly impaired compared with age- and sex-matched controls [8]. Patients with secondary insufficiency were slightly more impaired than those with primary adrenal insufficiency.

Unmasking arginine vasopressin deficiency — An unusual side effect of glucocorticoid replacement is the unmasking of previously subclinical arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus), leading to polyuria [9]. Correction of cortisol deficiency can increase the blood pressure and renal blood flow and, in patients with partial AVP-D, reduce the secretion of vasopressin. All of these effects increase urine output. (See "Urine output in arginine vasopressin disorders (diabetes insipidus)".)

Need for mineralocorticoid coverage — Unlike primary adrenal insufficiency, mineralocorticoid replacement is not necessary in hypopituitarism. Angiotensin II and potassium, not ACTH, are the major regulators of aldosterone secretion [10,11].

Adrenal androgen replacement — In females with secondary adrenal insufficiency, exogenous dehydroepiandrosterone (DHEA) replacement may have a small beneficial effect on psychological well-being. However, these data are from females with panhypopituitarism, who have combined ACTH and gonadotropin deficiency, and therefore adrenal and ovarian androgen deficiency. There are no data in females with isolated ACTH deficiency. (See "Treatment of adrenal insufficiency in adults", section on 'Androgen replacement therapy for selected females'.)

TSH DEFICIENCY — Thyroid-stimulating hormone (TSH) deficiency results in thyroxine (T4) deficiency and is treated with T4 (levothyroxine). The factors that influence dosing are similar to those of primary hypothyroidism. However, treatment of secondary hypothyroidism differs in two ways:

●T4 should not be administered until adrenal function, including corticotropin (ACTH) reserve, has been evaluated and either found to be normal or, if deficient, treated. In a patient with coexisting hypothyroidism and hypoadrenalism, treatment of the hypothyroidism alone may increase the clearance of the little cortisol that is produced, thereby increasing the severity of the cortisol deficiency.

●Measurement of serum TSH cannot be used as a guide to the adequacy of T4 replacement. We suggest starting with a weight-based T4 dose of 1.6 mcg/kg. The American Thyroid Association (ATA) recommends adjusting the dose to maintain the serum free T4 concentration in the upper half of the reference range [12]. We suggest that the goal should be a serum free T4 level slightly higher than mid-normal, based on the rationale that only T4 is being given. (See "Central hypothyroidism", section on 'Treatment'.)

LH AND FSH DEFICIENCY — Treatment of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency depends upon sex and whether or not fertility is desired.

Males — Testosterone replacement is indicated in males who have secondary hypogonadism and are not interested in fertility. The choice of treatment does not differ from that in males with primary hypogonadism. The adequacy of treatment should be determined by measuring serum testosterone, not LH. (See "Testosterone treatment of male hypogonadism", section on 'Monitoring'.)

Males with secondary hypogonadism who wish to become fertile can be treated with gonadotropins if they have pituitary disease or with either gonadotropins or gonadotropin-releasing hormone (GnRH) if they have hypothalamic disease. (See "Induction of fertility in males with secondary hypogonadism".)

Females — Females with hypogonadism due to pituitary disease who are not interested in fertility should be treated with estradiol-progestin replacement therapy. The goal of treatment is not the same as in postmenopausal females, in whom the goal is to give estradiol and progestin only if necessary to relieve hot flashes. Instead, the goal of treatment of females of premenopausal age is similar to that of replacement of thyroxine (T4) and cortisol, ie, to replace the missing hormones as physiologically as possible.

Toward this end, we suggest treatment with estradiol (the estrogen the human ovaries secrete) transdermally, so estradiol is absorbed into the systemic circulation (as when it is secreted by the ovaries). Females with an intact uterus must also take a progestin to avoid the risk of endometrial hyperplasia or carcinoma. We recommend that females with hypopituitarism take transdermal estradiol continuously throughout the month and take a progestin on days 1 to 12 of the calendar month. For females who have a history of or who develop cyclic mood changes (premenstrual syndrome or premenstrual dysphoric disorder), a continuous daily regimen of both estradiol and a lower dose of progestin is better tolerated. (See "Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual dysphoric disorder".)

These regimens are similar to those used for treatment of primary ovarian insufficiency. For females who do not tolerate transdermal preparations (or who prefer oral regimens), oral estradiol is an effective and inexpensive alternative. (See "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Suggested estrogen regimens'.)

Females with secondary hypogonadism who wish to become fertile should be offered ovulation induction with gonadotropins. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Management' and "Overview of ovulation induction", section on 'Gonadotropin therapy'.)

Androgen replacement — Serum androgen concentrations in females with hypopituitarism, particularly those with both gonadotropin and corticotropin (ACTH) deficiency, are significantly lower than those in normal females [13]. The role of exogenous testosterone therapy in these individuals is unclear, but it is not recommended. The role of adrenal androgen replacement is also unclear. (See 'Adrenal androgen replacement' above.)

The effect of exogenous testosterone therapy in females with androgen deficiency due to hypopituitarism was addressed in a study of 51 such patients taking exogenous estrogen orally. Testosterone replacement was administered transdermally at doses of 150 to 300 mcg/day for one year, resulting in serum free testosterone concentrations in the normal range and increased mean bone mineral density of the hip and radius, but not the spine [14]. Other effects included an increase in fat-free mass and thigh muscle area, and improvements in some aspects of mood, sexual function, and quality of life, as assessed by questionnaires. One-third of the females receiving testosterone developed acne, but no patients developed hirsutism or other hyperandrogenic side effects. Androgen therapy in females is discussed in more detail separately. (See "Overview of androgen deficiency and therapy in females" and "Overview of sexual dysfunction in females: Management", section on 'Androgens'.)

GROWTH HORMONE DEFICIENCY — We do not recommend recombinant human growth hormone (GH) as routine treatment for all patients with adult-onset GH deficiency, because the weak clinical benefits do not seem to warrant daily injections and high cost. The clinical manifestations, diagnosis, and treatment of GH deficiency in adults is reviewed in detail separately. (See "Growth hormone deficiency in adults".)

The availability of several recombinant human GH preparations for treating adults with GH deficiency allows clinicians to prescribe this treatment. Patients with GH deficiency acquired as an adult must, to be reimbursed by insurance companies in the United States, meet at least two criteria for therapy: a low insulin-like growth factor-1 (IGF-1) concentration or a poor GH response to at least two standard stimuli, and hypopituitarism due to pituitary or hypothalamic damage. The criteria are different in children in whom GH is required for normal growth. (See "Treatment of growth hormone deficiency in children".)

PROLACTIN DEFICIENCY — The only known presentation of prolactin deficiency is the inability to lactate after delivery, for which there is currently no available treatment. Recombinant human prolactin (r-hPRL), although not commercially available, has been used experimentally in an open-label, pilot study of five females with prolactin deficiency due to Sheehan syndrome or other causes [15]. Prolactin deficiency was defined as baseline or peak serum prolactin levels below the normal range for their postpartum date and production of less than 8 mL of milk per day. Subcutaneous administration of r-hPRL every 12 hours for 28 days increased mean milk production from 3.4±1.6 mL to 66.1±8.3 mL per day.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Panhypopituitarism (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Treatment of patients with hypopituitarism is the sum of the treatments of each of the individual pituitary hormonal deficiencies detected when a patient with a pituitary or hypothalamic disease is tested. The treatments of corticotropin (ACTH), thyroid-stimulating hormone (TSH), and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiencies are in many ways the same as the treatments of primary deficiencies of the respective target glands, but in other ways they differ.

●ACTH deficiency, which results primarily in cortisol deficiency, is treated with hydrocortisone in an amount and timing to mimic the normal pattern of cortisol secretion. A modified-release formulation is available in some countries. (See 'ACTH deficiency' above and "Treatment of adrenal insufficiency in adults", section on 'Hydrocortisone (preferred glucocorticoid)'.)

●TSH deficiency, which results in thyroxine (T4) deficiency, is treated with T4 (levothyroxine). T4 should not be administered until adrenal function, including ACTH reserve, has been evaluated and either found to be normal or treated.

Measurement of serum TSH cannot be used as a guide to the adequacy of T4 replacement therapy. We suggest starting with a weight-based T4 dose of 1.6 mcg/kg. The dose should be adjusted according to the serum T4 or free T4 values. We suggest a goal of serum T4 level slightly higher than mid-normal, based on the rationale that only T4 is being given. (See 'TSH deficiency' above and "Central hypothyroidism", section on 'Treatment'.)

●Gonadotropin deficiency in males who are not interested in fertility should be treated with testosterone replacement. In males who do wish to become fertile, the treatment is gonadotropins. (See 'Males' above and "Induction of fertility in males with secondary hypogonadism", section on 'Gonadotropin therapy'.)

Females with gonadotropin deficiency who are not interested in fertility should be treated with estradiol transdermally and a progestin. In females who are interested in fertility, gonadotropin therapy is the treatment of choice. (See 'Females' above and "Overview of ovulation induction", section on 'Gonadotropin therapy'.)

●The role of androgen therapy in females with hypopituitarism has not been established. (See 'Adrenal androgen replacement' above and 'Androgen replacement' above.)

●We do not recommend recombinant human growth hormone (GH) as routine treatment for all patients with adult-onset GH deficiency. The clinical manifestations, diagnosis, and treatment of GH deficiency in adults are reviewed in detail separately. (See 'Growth hormone deficiency' above and "Growth hormone deficiency in adults".)