Shieldhealthcare

Hyperprolactinemia: a concern in infertility

Introduction

Prolactin is a lactogenic hormone derived from pituitary and play a significant role in a variety of reproductive functions. The hormone is synthesized and released by lactotroph cells of anterior pituitary. It is structurally like human growth hormone (HGH) and human placental lactogen (HPL)1.

Prolactin molecule

Prolactin is a 23 kDa polypeptide hormone (198 amino acid) synthesized in the lactotroph cells of the anterior pituitary gland. Its secretion is pulsatile and increases with sleep, stress, food ingestion, pregnancy, chest wall stimulation, and trauma.

Synthesis and Release

Hormone is synthesized and released by lactotroph cells of anterior pituitary. Unlike other tropic hormones, release of prolactin (PRL) is controlled primarily by negative inhibitory mechanism of dopamine. It negatively controls the secretion of other pituitary hormones responsible for gonadal function like LH, FSH. 

Several factors exert a stimulatory effect on prolactin secretion especially 

  • Thyrotropin releasing hormone (TRH)
  • Vasoactive intestinal peptide (VIP)
  • Perhaps GnRH

Important clinical manifestations are associated with hyperprolactinemia with elevation of TRH secretion that occurs primarily in hypothyroidism 2.

Prolactin homeostasis is reflected by prolactin itself feeding back on the dopamine releasing neurons.

Extra pituitary sources of PRL

These are PRL secreted by breast, endometrium, and decidua

Breast

It’s persistent suckling PRL levels remain elevated. Lactational amenorrhoea continues, and this works as a natural contraceptive method 3 

Endometrium and Decidual PRL

Specialized endometrium of the luteal phase of menstrual cycle.

Human decidual tissue of placental source synthesized and release PRL

Causes of hyperprolactinemia 4,5

  1. Impaired dopamine delivery
  2. Medication

Neuroleptics: Haloperidol, Phenothiazine

Antihypertensive: Calcium-channel blockers and methyldopa

Psychotropic drugs: Tricyclic antidepressant and SSRI

Antiulcer agent: H2 antagonist

Opiates

  1. Neurogenic: Chest wall injury, breast stimulation, breast feeding
  2. Pituitary stock compression: Pituitary tumours like adenoma, acromegaly etc
  3. Enhanced lactotrophic cell stimulation

Hypothyroidism (increased TRH)

Pituitary adenoma (Prolactinoma)

Hypophysitis

Oxytocin

PCOS

VIP

  1. Impaired hepatic and renal clearance

Prolactin cleared less rapidly from systemic circulation thus increasing the blood level. 

  1. Sometimes there may be abnormal molecules of PRL (big big prolactin). They are not significant in clinical diagnosis.

Hyperprolactinemia in infertility

Hyperprolactinemia is amongst the most common causes of secondary amenorrhoea. If present in pre menarche years may present as delayed puberty primary amenorrhoea. They are the candidates who might present as primary infertility. So, serum PRL should be checked with amenorrhoea (<15-20ng/mL). Circulating PRL can increase transiently during C exercise, breast stimulation and means. Mildly elevated PRL levels should be repeated before the diagnosis of hyperprolactinemia. 

Hyperprolactinemia results in anovulation and amenorrhoea: – Stimulates a generalized increase in hypothalamic dopaminergic neuronal activity to suppress PRL secretion but also inhibiting GnRH neurons leading to disruption of GnRH pulse rhythm→ Low GnRH

Consequences of GnRH pulsatility owing to excess PRL may leads to subtle ovulatory disfunction to anovulation or hypogonadotropic hypogonadism.

Mild hyperprolactinemia (20-50ng/mL) 

  • Short luteal phase resulting from poor preovulatory follicular development

Moderate Hyperprolactinemia (50-100ng/mL)

  • Frequently cause oligomenorrhoea or amenorrhoea

Higher level (>100ng/mL)

  •  Frank hypogonadism with low estrogen level
  • Clinical consequence: Genitourinary atrophy, Loss of bone mass

Action on adrenal gland

Prolactin receptors having identified in human adrenal gland and PRL can increase adrenal DHEA production invitro. Prolactin stimulates the adrenal gland which leads to increase in androgen production results in chronic anovulation.

Action on ovaries

Elevated PRL levels result in a spectrum of ovulatory dysfunction ranging from short luteal phase to anovulatory cycles.

Hyperprolactinemia leads to abnormal gonadotropin secretion 

Abnormality in GnRH pulsatility is the principal drivers of abnormal gonadotropin secretion pattern that commonly encounter in PCOS as well as obesity related ovulatory dysfunction.

Male factors

Hyperprolactinemia from any cause and treatment with GnRH analogues (Prostatic cancer) GnRH analogues, androgen (anabolic steroids), glucocorticoids or opiates can suppress gonadotropin secretion. Critical illness or injury (head injury, chronic systemic illness (type II DM) or malnutrition also have been associated with

hypogonadotropic hypogonadism.

Diagram Description automatically generated

Fig 1: Overview of diagnosis and management of hyperprolactinemia

Diagnosis & treatment

A blood test is used to detect excess prolactin levels. If prolactin levels are high, more tests are usually done to check thyroid hormone. Normal thyroid hormone levels rule out hypothyroidism as a cause of hyperprolactinemia. 

If a prolactinoma is suspected, an MRI (magnetic resonance imaging) of the brain and pituitary is often the next step. 

Treatment for hyperprolactinemia

Treatment is based on the cause. Some people with high prolactin levels, but few have no signs and symptoms, do not need any treatment. 

Options for treating tumours include

Prescription medicines: Dopamine Agonists like bromocriptine and cabergoline decrease prolactin production. Bromocriptine is taken 2-3 times a day and Cabergoline is long acting and used twice weekly.

Surgery to remove a tumour: Surgery may be used if medicines have not been effective. Surgery is sometimes needed if the tumour is affecting vision.

Radiation: Rarely, if medicines and surgery have not been effective, radiation is used to shrink the tumour.

Hypothyroidism is treated with synthetic thyroid hormone, which should bring prolactin levels back to normal. If high prolactin levels are caused by prescription medications, other types of medications can be explored.

References

  1. Majumdar et al., Journal of Human Reproductive Sciences, Volume 6, Issue 3, Jul – Sep 2013.
  2. Benker G, Jaspers C, Häusler G, Reinwein D. Control of prolactin secretion. Klin Wochenschr 1990; 68:1157‑67.
  3. Nilsson LA, Roepstorff C, Kiens B, Billig H, Ling C. Prolactin suppresses malonyl‑CoA concentration in human adipose tissue. Horm Metab Res, 2009;41:747‑51.
  4. Hormone Health Network.”Hyperprolactinemia | Hormone Health Network.” Hormone.org, Endocrine Society, 28 October 2021, https://www.hormone.org/diseases-and-conditions/hyperprolactinemia.
  5. BN Chakravarty, Clinics in Reproductive Medicine and assisted Reproductive Technology, Vol-2, ISBN: 978-93-86217-66-0.
  6. Shlomo Melmed et al., The Journal of Clinical Endocrinology & Metabolism, 96(2), 2011, 273–288.

A picture containing person, wall, person, indoor Description automatically generated

Endorsed by,

Dr. Saktirupa Chakraborty

DGO., MD., FICOG

Consultant Visiting Gynaecologist/Obstetrician

Attached to IRM, AMRI Hospital, AMWI, Kolkata