Pituitary disorders and subfertility

Introduction

The pituitary gland, also called the master gland of the human endocrine system, is situated at the base of the skull within the sella turcica, a part of the sphenoid bone. Anatomically it is divided into two parts: (i) the anterior part, also called adenohypophysis, and (ii) the posterior part, also called neurohypophysis. The adenohypophysis part works closely with the hypothalamus to control the function of other glands including gonads.

Gonadotropin-releasing hormone (GnRH) is released from hypothalamus periodically in pulses to control the secretion of two gonadotrophin hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both control functions and maturation of reproductive organs as shown in Fig. 10.1 .

The hypothalamic–pituitary–gonadal axis (HPGA) plays a fundamental role in fertility, and any disorder affecting pituitary, being a central position in this axis, can cause fertility issues. HPGA can be altered by many factors including congenital and acquired causes as mentioned in Table 10.1 .

Disorders of women ovulation are among the common causes of subfertility and are classified by WHO into three groups. Approximately 10% of ovulatory disorders are secondary to HPGA defects and are categorized into group I. Group II constitutes around 85% of ovulatory disorders with normogonadotropic anovulation with predominantly polycystic ovaries, and group III includes disorders because of ovarian failure leading to hypergonadotropic hypogonadism.

A pituitary etiology should be considered in all patients whom initial workup points toward hypogonadotropic hypogonadism, i.e., low LH, FSH, and testosterone (Te)/estradiol (E2), or hyperprolactinemia. Most of these pituitary disorders are simple to manage medically with very good outcomes.

Approach to patients with subfertility

After a detailed history and examination, a preliminary workup in women with subfertility—but with regular cycles—is required to determine about their ovulation status by measuring serum progesterone levels during the midluteal phase (day 21). Serum progesterone with a level of ≥ 30 nmol/L is required to confirm the ovulation. In women with no ovulation, serum progesterone level < 10 nmol/L or with irregular cycles, amenorrhea or oligomenorrhea, a further hormonal workup to assess the FSH, LH, E2, TSH, and serum prolactin is required to determine the underlying cause of subfertility.

In men with subfertility, following a detailed history and examination, the foremost step is to obtain seminal fluid analysis. Semen sample should be collected with an abstinence of 2–5 days from ejaculation. At least two samples on two different days, preferably 1 week apart, are required, because of day-to-day variation in sperm concentrations. A further hormonal workup—morning Te, FSH, LH, TSH, and prolactin—is required in case of abnormal semen analysis.

Separate investigations for acromegaly and Cushing’s disease (CD) are required which would be disease specific, in addition to above initial subfertility work up. Magnetic resonance imaging (MRI) of the hypothalamic–pituitary region is mandatory in all cases with hypogonadotropic hypogonadism, pathological hyperprolactinemia, acromegaly, and CD.

Hyperprolactinemia and prolactinomas

Prolactin is a polypeptide hormone produced and secreted by the lactotroph cells of the anterior pituitary gland. In addition to its primary function of promoting lactation and breast development, it is associated with the reproductive system, immune system, behavioral changes, and also contributes to salt and water balance in the human body. Its secretion is controlled by various hormones and neurotransmitters through tonic inhibition by dopamine.

Hyperprolactinemia means a higher level of prolactin in the blood above the normal reference range. Usually, normal reference range for prolactin level is between 10 and 35 ng/mL, with a conversion factor of 1 ng/mL = 21.2766 μIU/mL. Hyperprolactinemia is a common disorder present in around 1% of the general population and 9%–17% of women with gonadal dysfunction. Causes of hyperprolactinemia vary from idiopathic, physiological, and pharmacological to pathological as described in Table 10.2 .

Prolactinomas are the benign tumor of pituitary lactotroph cells. These are the most common functioning pituitary adenomas with an estimated prevalence of 45 cases/100,000 population. They are more common in women with a women- to-men ratio of around 8:1, especially during reproductive age. In women, they are mostly microadenomas due to their early presentation with menstrual irregularities or galactorrhea, whereas in men, they present late and mostly have macroadenomas with hypogonadism.