Question: Are menstrual problems in women common in Cushing’s? 

Reproductive problems are common in patients with Cushing’s disease and Cushing’s syndrome. Women may experience amenorrhea ( a complete lack of menses), or irregular periods. This dysfunction typically results from the effects of the high levels of adrenal gland hormones to suppress the normal pituitary hormones LH and FSH, that regulate reproductive function. The high levels of cortisol made by the adrenal glands and the high levels of male hormone production, which may also accompany the syndrome, may cause this.

In patients with Cushing’s disease and pituitary tumors, a tumor of large size may inhibit normal pituitary function by its mass (compression of the normal pituitary). However, this is less common since the majority of pituitary tumors in this disorder are small microadenomas i.e. less than 1 centimeter in size and are unlikely to be of sufficient size to destroy the normal gland. Rarely, the tumor may also make another hormone, prolactin, which can also inhibit normal menstrual function and women may experience galactorrhea ( nipple discharge from the breasts). The high levels of androgens (male hormones) that are overproduced by the adrenal glands may also lead to hirsutism (excess body hair) and acne. Reproductive disorders are often an early sign of Cushing’s Syndrome.

Question: Do men experience reproductive problems as well?

 Yes. A decrease in libido and/or erectile dysfunction are common. Complete impotence may also accompany this disorder. The most important male hormone, testosterone, is produced primarily by the testes in men. High levels of adrenal steroids such as cortisol in Cushing’s syndrome can directly suppress the ability of the testes to make testosterone. In addition, high levels of cortisol and related hormones also interfere with the ability of the normal pituitary gland to secrete LH and FSH, the two pituitary hormones needed for normal male reproductive function.

Question: Are differences observed between pituitary and adrenal Cushing’s patients?

Patients with both syndromes produce excess cortisol. However, when the disease is caused by a pituitary tumor, the direct effects of the pituitary tumor itself must be considered. If the primary tumor is in the adrenal gland, there may be differences in the pattern of hormone secretion. All forms of this disease, however, can cause reproductive problems.

Question: What tests are done to determine whether there is reproductive dysfunction in women and what is usually measured?

In premenopausal women, menstrual function should be evaluated as well as clinical symptoms of excess androgens (male hormone production) such as excess hair or acne. In a women having regular periods no specific tests are needed to assess menstrual function. Male hormone levels such as testosterone, free testosterone (the amount of testosterone that acts directly on tissues in the body) and DHEA-S ( an adrenal androgen) may be determined.

In an amenorrheic women ( no menstrual periods), the two pituitary hormones LH and FSH may be measured along with an estradiol (estrogen level) to determine how much estrogen the ovaries are producing. Menstrual disorders combined with symptoms such as hirsutism, acne, weight gain, a buffalo hump and a moon face, should cause gynecologists to consider Cushing’s as a cause.

In cases of suspected pituitary disease, a prolactin level may also be drawn. This pituitary hormone may be elevated in a small number of patients and can also interfere with normal menstrual function. The number and type of tests ordered also depends upon whether a patient is still under evaluation to make the diagnosis or is about to be treated.

Question: Do normal periods usually resume after a cure?

If the normal part of the pituitary gland that controls reproductive function has not been damaged by the tumor itself, or affected by the surgery, menstrual periods would be expected to return. However, other medications used by the patient, post-operative illness and stress, may all impact on reproductive function. In a cured patient, if menstrual function has not returned after 3-4 months in a non-pregnant patient, further tests should be done to assess the problem and determine optimal therapy.

Question: If a patient is not making female hormones following surgery, what medications do they usually take and why?

If tests indicate that the pituitary gland is not functioning, the patient should discuss hormone replacement with her physician. This is critical. Women with Cushing’s syndrome often have osteoporosis because of their disease and maintaining normal amounts of estrogen is essential in preserving bone mass. Low levels of estrogen in a pre-menopausal women may also lead to higher cardiovascular risk long-term, decreased libido, sleep disturbances and mood changes. There are many forms of estrogen replacement therapy given. The specific type and dose should be discussed with a physician. In most young women requiring hormone replacement, a birth control pill is a convenient method of providing hormone replacement.

Question: Will someone who is hypopituitary and taking replacement female hormones have difficulty becoming pregnant?

Women with hypopituitarism typically will need to undergo ovulation induction i.e. receive hormone treatment to induce pregnancy. This requires treatment by an experienced reproductive endocrinologist but the results are often excellent.

Question: How is return of reproductive function in men assessed?

In men, in addition to monitoring symptoms such as energy level, muscle strength, libido and erectile function, blood tests for testosterone and/or free testosterone are typically done. A man who has had a low testosterone level and is now cured may take up to 3 months for levels to return to normal. If levels are still low after three months, therapy with testosterone should be discussed with the patient’s physician. Testosterone in men is important for normal sexual function and is also essential in preventing muscle loss and osteoporosis. Men with hypopituitarism who are interested in fertility require special hormone treatments to restore normal testicular function.

Author: Dr. Anne Klibanski, MD (Spring, 2000)

Editor’s Note: Dr. Anne Klibanski is Chief of the Neuroendocrine unit at Massachusetts General Hospital in Boston, MA. Dr. Klibanski has been involved in the treatment and research regarding Cushing’s and other pituitary tumors for a number of years.