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 .
|A. Pituitary adenomas: |
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 .
|A. Idiopathic |
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.
Fertility and reproductive function in hyperprolactinemia
Hyperprolactinemia is frequently found in infertile women compared to fertile women with a prevalence of around 48%–51.7% in infertile women and up to 11% in infertile men. A high level of prolactin is associated with inhibition of GnRH secretion from the hypothalamus and the low secretion of LH and FSH from pituitary gland. In addition to hypothalamic–pituitary effect, high prolactin has direct gonadal effects at several other levels including ovarian estrogen production, maturation of follicles, ovulation, luteinization, and functioning of corpus luteum. In men, it has a direct effect on Te production and spermatogenesis via prolactin receptors expressed on Leydig and Sertoli cells.
These effects result in low estrogen and Te; thus, in women, it can present with amenorrhea, galactorrhea, decreased libido, and subfertility, while in men, it can present with decreased libido, erectile dysfunction, subfertility, gynecomastia, and rarely galactorrhea.
Because of long-term anovulation and an insufficient luteal phase observed in these women, hyperprolactinemia has been associated with defects in endometrial growth along with a failure of implantation. In men, serum prolactin has been studied to have an inverse correlation with the sperm count.
After a detailed medical history and examination that focuses on all causes of hyperprolactinemia ( Table 10.2 ), a further workup should be done to exclude other causes of hyperprolactinemia. The MRI of the hypothalamic–pituitary region is mandatory in all cases of hyperprolactinemia in which no obvious cause is identified. Treatment is indicated in all symptomatic patients with hyperprolactinemia if even no lesion is identified on initial MRI or in patients with macroadenomas on MRI.
Treatment goals for the patients with prolactinomas are the normalization of serum prolactin level, decrease in the size of pituitary adenoma to reduce mass effects, restoration of gonadal dysfunction, and fertility.
Dopamine agonists (DAs) are the most effective treatment option in patients with prolactinomas by reducing the prolactin levels, thus restoring gonadal dysfunction and fertility issues. Cabergoline is preferred over bromocriptine because of its better efficacy, convenient dosage, and better tolerability. In one of the largest follow-up studies of 459 women with hyperprolactinemic amenorrhea, resolution of the ovulatory cycle or pregnancy was reported in 72% of the women who were managed with cabergoline and 52% of the women who were managed with bromocriptine. Because of its shorter half-life and relatively a safer option, bromocriptine is preferred over cabergoline for pregnancy induction.
In patients with microadenomas, after normalization of prolactin and restoration of ovulation, pregnancy is usually delayed for up to three to four regular menstrual cycles, time sufficient to predict pregnancy in case of any missed cycle. While in patients with macroadenomas, pregnancy is usually delayed until the size of the tumor decreased to microadenoma or it becomes confined to sella, so that they do not have to continue DAs during pregnancy.
In those patients, who do not ovulate despite normalization of prolactin levels, cyclical administration of clomiphene citrate, gonadotropins, or pulsatile GnRH can be combined with DAs to increase the success rates of fertility.
Acromegaly is a rare chronic multisystemic disorder of pituitary origin, with an incidence of 0.2–1.1 cases per 100,000 population with an estimated prevalence of 2.8–13.7 cases per 100,00 population annually. In most of the cases, it is caused by growth hormone (GH) secreting pituitary adenoma with an equal ratio in men and women. In a few cases, it can result from ectopic GH secretion or secondary to growth hormone-releasing hormone adenoma of hypothalamic origin. Because of its insidious onset, it is usually diagnosed around the age of 40, with a delay of 4–5 years after the disease onset.
Fertility and reproductive function in acromegaly
Gonadal dysfunction is a common clinical entity in both sexes with acromegaly and has been reported in around 59%–70% of women with this condition, while in data on men, information regarding this effect is lacking. Hypogonadism in patients with acromegaly can be explained by various mechanisms, these include anatomical compression of HPGA by mass effect, hyperprolactinemia caused by GH and prolactin cosecretion, or by dopamine inhibition by stalk compression. The lactotrophic effect of GH (spillover effect) may influence gonadal dysfunction.
In addition to these effects, recent data suggest that GH and insulin-like growth factor 1 (IGF-1) have also a direct inhibitory effect over ovarian function. IGF-1 locally increases androgen production from theca cells of ovarian follicles, resulting in hyperandrogenemia and polycystic ovarian morphology along with menstrual irregularities.
In one study on men with acromegaly, it was found that serum Te was below normal in 42.8%, and dihydrotestosterone (DHT) was low in 65.7% along with low seminal volume, total sperm count, sperm count per mL, normal morphology, vitality, total motility, and forward progression.
Spontaneous pregnancy in untreated patients is very rare, less than 158 reported in the literature. With the advancement in surgical, medical, and reproductive techniques, pregnancies have been reported more frequently than before in this group of patients.
Women with this condition, who want to get pregnant, should be advised to undergo treatment of acromegaly first to avoid the expansion of pituitary adenoma before pregnancy, normalization of hyperprolactinemia, GH, and IGF-1 levels to maximize their fertility potential. They should also be assessed for the deficiency of other pituitary hormones and should be adequately replaced before undergoing any fertility treatment.
Men with the condition, after treatment and normalization of GH/IGF-1 levels, have been reported to show an improvement in Te and DHT levels with an increase in the volume of the semen along with an improvement in other parameters such as sperm count and motility.
CD is a rare endocrine disorder of the pituitary origin characterized by chronic hypercortisolemia. The incidence of CD is 1.2–2.4/million population per year with an estimated prevalence of around 40 cases/million population. CD is more common among women and is mostly diagnosed during the age of 40–60 years, thus rarely encountered in the fertility clinics.
Fertility and reproductive function in Cushing’s disease
Hypercortisolemia can affect the reproductive system, resulting in menstrual irregularities in more than two-thirds of women with this condition. Most of the women with CD present clinically with similar signs and symptoms that are observed in young women with PCOS, irregular cycles, hirsutism, acne, obesity, hyperandrogenism, low SHBG levels, and an increased gonadotropin response to GnRH.
Hypogonadism in patients with CD can be explained by various mechanisms, such as inhibition of HPGA by both chronic hypercortisolemia and adrenal hyperandrogenism and also by high levels of adrenocorticotropic hormone and corticotropin-releasing hormone, resulting in low levels of LH and estrogen and thus chronic anovulation. In addition, ovaries in CD have been reported to have decreased size, a low number of follicles, absence of luteinization, and fibrosis.
In men, information regarding the effects of CD on testicular function is very limited and thought to be due to sparse Leydig cells, the thickened basement of seminiferous tubules, and low spermatogenesis on histology. If patients have macroadenoma, hypogonadism and fertility may further be affected by hyperprolactinemia due to stalk effect, though less common in CD as mostly they are associated with microadenoma.
Nonfunctioning pituitary adenomas
Nonfunctioning pituitary adenomas (NFPAs) is the second most common cause of pituitary adenoma after prolactinomas with an estimated prevalence of 7–41.3 cases/100,000 population. NFPAs are rare during reproductive age as their peak occurrence has been reported between 40 and 80 years.
NFPAs do not have any hormonal activity and are thus detected clinically late with symptoms, such as headaches, visual defects, cranial nerve palsies, and hormonal deficiencies. Endocrine manifestations of NFPAs depend upon the size and degree of compression by NFPAs over normal pituitary tissues. They can present clinically with a varying degree of hormonal deficiencies from partial hypopituitarism (37%–85%) to panhypopituitarism (6%–29%).
Hypogonadotropic hypogonadism is one of the common hormonal deficiencies in around 38%–72% of patients with clinical symptoms of low libido, erectile dysfunction, and disorders of menstruation. Hyperprolactinemia observed in NFPAs is usually mild and occurs because of blockage of dopaminergic inhibition of lactotroph by pituitary adenoma, called a stalk effect.
During a normal pregnancy, pituitary size is expected to increase by an average of 120% with a 40% increase in lactotrophs. The effect of pregnancy on the actual size of NFPAs is a less expected phenomenon, though lactotrophic hyperplasia can present with chiasmal compression. Due to advances in the treatment of pituitary tumors and subfertility, many women are getting pregnant with pituitary disorders. In recently reported two case series, 23 cases of NFPAs have been reported in pregnancies with good pregnancy outcomes but with an increased rate of cesarean section deliveries than controls.
The management of subfertility in patients with pituitary disorders requires shared care by endocrinologists, neurosurgeons, and fertility specialists. Prolactinomas are the most common pituitary disorders linked with subfertility, with a positive outcome in most cases with the appropriate treatment. For other causes of subfertility such as acromegaly and CD requires management of underlying disease itself as surgical removal of adenoma for rapid restoration of endocrine dysfunction and fertility outcomes. Medical therapy is usually discontinued upon confirmation of pregnancy with close monitoring of signs and symptoms of compression throughout the pregnancy. In patients with NFPAs, adequate hormonal replacement is the aim to preserve fertility along with monitoring for new hormone deficiencies and increase in thyroid hormones and glucocorticoids requirements during pregnancy.