Prevalence of hyperprolactinemia in infertile women and its association with hypothyroidism

INTRODUCTION

Female infertility accounts for 37% of all infertile couples & among them most are due to ovulatory disorder, and is often associated with dysregulation of hormonal network.¹ Presence of abnormally high values of prolactin,>25µg/L is termed as hyperprolactinemia which is one of the most common endocrinological disorder of the hypothalamopituitary axis affecting fertility.^2-4 Hyperprolactinemia affects the fertility potential by impairing pulsatile secretion of GnRH and interferes with the action of gonadotropins at the ovarian level so interfering with ovulation.^5,6 Hyperprolactinemia causes galactorrhea along with menstrual and ovulatory disturbances. It is present in two thirds of women with both galactorrhea and amenorrhea. So estimation of serum prolactin levels should be done in unexplained infertility, any menstrual irregularity with or without hirsutism, galactorrhea with or without amenorrhea, luteal phase defects and anovulation.⁷ Mild hyperprolactinemia can cause infertility even with regular menstruation.⁸ Women with galactorrhea and hyperprolactinemia might have primary hypothyroidism. Hypothyroidism stimulates increased secretion of TRH which stimulates thyrotrophs and lactotrophs, causing increase in the levels of both TSH & prolactin.⁹ This study was conducted to find out the incidence of hyperprolactinemia in female infertility after excluding tubal factor and male factor and to find its association with hypothyroidism.

METHODS

Study design

Hospital based analytical cross sectional study

Study period

One and half years from April 2014 to September 2015.

Study population

300 women who attended the outpatient department, OBGY, ACS Medical College, Chennai, India.

Inclusion criteria

Women with primary and secondary infertility.

Exclusion criteria

1. Male factor infertility, female factors-tubal factor, urogenital tract anomalies and obvious organic lesion in pelvis.

2. History of thyroid disease/thyroid surgery/thyroid medication.

3. Women unwilling to participate or sign the informed consent.

Ethical considerations

Informed consent was obtained from all the participants at the start of the study. Ethical clearance was taken from the institutional ethical committee before starting the study.

Proforma

1. Detailed clinical history: Age, menarche, menstrual cycles, acne, hirsutism, marital history, drug history, galactorrhea and any visual disturbances.

2. Clinical examination: Anthropometric measurements of weight, height, BMI, breast, abdomen and pelvic examination

3. Investigations: USG abdomen and pelvis, hysterosalpingography, husband’s semen analysis, serum TSH and free T₄ levels by radio immuno assay (RIA) and serum prolactin levels.

With regard to raised prolactin (PRL) levels, as per WHO guidelines, PRL level >25μg/l was considered as hyperprolactinemia.¹⁰

Based on Canadian medical association, Hyperprolactinemia was categorized into¹¹

1. Mild 26-50µg/L

2. Moderate 51-75µg/L

3. Marked >100µg/L

Recommendations for diagnosis of hyperprolactinemia¹²

1. A single measurement of serum prolactin level can confirm the diagnosis if the level is above the upper limit of normal and the sample was obtained without excessive venipuncture stress. Dynamic testing of prolactin secretion is not recommended to diagnose hyperprolactinemia.

2. Macroprolactin evaluation is recommended in patients with asymptomatic hyperprolactinemia.

BMI - ICMR guidelines (2008) ¹³

1. Normal - 18 - 22.9 kg/m2

2. Overweight - 23 -25 kg/m²

3. Obese - > 25 kg/m²

In our study, we have analysed the prevalence of hyperprolactinemia among primary and secondary infertile women, potential socio-demographic risk factors, clinical and biochemical parameters associated with hyperprolactinemia. Categorical data were analysed with the odds ratio, chi square test and the p value of < 0.05 was considered statistically significant. SPSS software was used for statistical analysis.

RESULTS

Serum prolactin level and prevalence of hyperprolactinemia in infertile females

Among the 300 infertile females, 74 had elevated serum prolactin level. The prevalence of hyperprolactinemia (>25 µg/L) was 24.67% (74/300) (Figure 1). Elevated serum prolactin level was noted in 25.5% (61/239) of primary infertility and 21.31% (13/61) of secondary infertility females (Figure 3). The mean serum prolactin level in hyperprolactinemic women was 84.83µg/L. Of the 300 patients, 239 (60%) had primary infertility and 61 (40%) had secondary infertility.

Out of the 74 hyperprolactinemic females, 59 had serum prolactin levels of 26-100 µg/L which contributes to 36.89% (59/300), 14 females had 101-200µg/L (9.52%). Only one female had serum prolactin >200µg/L but her brain imaging was found to be normal.

Socio-demographic factors of infertile females

Age

Most of the females were 26-30 years (51.35%) in both infertile groups (OR 1.4; 95% CI 0.79-2.46) followed by 18-25years (29.73%), 31-35years (16.22%) and >35years 2.7%. The mean age in primary infertile females was 26.4yrs and in those with secondary infertility was 31.8yrs. The mean duration of primary and secondary infertility was 2.56years &3.42 years respectively.

Family history of hyperprolactinemia

Only 3.33 % (16 patients) of infertile women (Table 1) showed positive family history of hyperprolactinemia. Among the elevated serum prolactin group, only 4 females (5.41%) were having family history of hyperprolactinemia. In similar to other studies, which shows that no association exists between elevated serum prolactin level and family history of hyperprolactinemia, our statistics also showed a negative correlation (OR - 2.09; 95% C.I –0.57-7.64).

Hypothyroidism and elevated serum prolactin levels

The incidence of hypothyroidism in infertility was 27.33% (82/300) with 95% CI: 22.29-32.37 (Table-2). Presence of hypothyroidism in hyperprolactinemia was 25.5% i.e.19 out of 74 (OR 1.12; 95% CI: 10.62-2.03) Table -3. The mean serum prolactin level in hypothyroid women was 27.36µg/L. The ratio of proportions between hyperprolactinemia and hypothyroidism was 4:1 i.e. in every four hyperprolactinemic females one had hypothyroidism. The statistical correlation between hypothyroidism and elevated prolactin level was insignificant (p value 0.71) as seen in Table 3.

Galactorrhea and hyperprolactinemia

Galactorrhea was present in 8% (24 females) of infertile females with 95% CI 4.93-11.07 (Table -2), among them 15 were hyperprolactinemic. Galactorrhea was either the chief complaint or was detected on clinical examination. The mean serum prolactin level in women with galactorrhea was 54.58µg/L. Out of the 74 women with hyperprolactinemia, 15(20.27%) had galactorrhea. We found strong correlation between galactorrhea and elevated serum prolactin (OR 6.13 with 95% CI 2.56-14.71) with significant p value 0.000009 (Table 3).

BMI and obesity

BMI >25 was present in 78 infertile females, that is 26% of total (95% CI 21.04-30.96). Out of the 78females, 35(47.3%) were hyperprolactinemic (OR 3.82; 95% CI 2.17-6.72). Association between obesity and hyperprolactinemia was significant with p value of 0.000003 (Table 3).

Menstrual dysfunction

Normal menstrual cycles were present in 75.4% (226/300) infertile patients, remaining 24.6% (74/300) showed some menstrual abnormality with 95% CI 19.79-29.55. Among the 74 patients with abnormal menstruation, 22 (29.7%) patients were hyperprolactinemic. In females with elevated prolactin, 70% had normal menstrual cycles, oligomenorrhea was present in 16.2% and menorrhagia in 13.5% and none had amenorrhea (Figure 2). Anovulation present in 29.73% (OR 1.42, 95% CI 0.79-2.55) of hyperprolactinemic females. This finding was contrary to other studies.

In hysterosalpingography, all the patients had patent fallopian tubes as none with tubal factor infertility was included in this study. Ultrasonogram didn’t show any obvious organic pelvic pathology which causes infertility.

Fifteen women (19.67%) had prolactin levels >100ng/mL, 12 with primary infertility and 3 with secondary infertility. All the 15 were advised CT scan or MRI and pituitary adenoma was found in one female with serum prolactin level 165ng/mL. The remaining 14 showed normal findings.

The most common cause of hyperprolactinemia in our study was idiopathic, followed by primary hypothyroidism.

DISCUSSION

Hyperprolactinemia is one of the most common endocrinological disorders affecting fertility.¹⁴ The understanding that hyperprolactinemia not only manifests as galactorrhea and amenorrhea but also causes gonadal dysfunction and infertility led to the estimation of prolactin in infertile females.

The prevalence of hyperprolactinemia according to various studies, in Avasti et al study 46% (111 patients), In Goswami et al study 41% (160 patients), In Akhter & Hassan et al study 37.5%, Salah et al study 33.3% (150 patients), In Indu Verma et al study 13.7% (54 out of total 394 patients), in our study prevalence of hyperprolactinemia was 24.67%.^8,15-17 Stress is one of the factor affecting prolactin secretion, variable prevalence may be due to different stress levels in various regions.

In Akhter & Hassan et al study 43% females had primary infertility and 22% had secondary infertility.¹⁶ In Muhammad et al study primary infertility was 55.7% and secondary infertility was 44.3%.¹⁸ In Avasti et al study on 111 infertile pts showed 60% (67 females) primary and 40% (44 females) secondary infertility.⁷ Similar results were found in Sharma et al study.¹⁹ In our study, there were 79.6% (239) women with primary infertility and 20.4% (61) women with secondary infertility. Secondary infertility females may seek consultation less frequently because they already had pregnancy. Among the 239 primary infertility and 61 secondary infertility females, 25.5% (61/239) and 21.3% (13/61) were hyperprolactinemic respectively.

Hyperprolactinemia decreases the GnRH pulsatile release and impairs FSH, LH secretion. It also affects the steroidogenic activity of ovarian follicles and causes inadequate progesterone secretion in luteal phase ^(18). All these results in luteal phase defect, inconstant ovulation and chronic anovulation. Luteal insufficiency impairs endometrial growth and affects the implantation of embryo.²⁰ This accounts for 3–10% of infertility and two thirds of these females had hyperprolactinemia.²¹ In hyperprolactinemic infertility, the best treatment to increase conception rate is to lower prolactin secretion with dopaminergic drugs.²²

Association between hypothyroidism and hyperprolactinemia in our study was 25.5% which is similar to Avasti et al study.⁷ In Chowdhury and Goswami et al study 16.6%, Singh et al study 57%, Indu Verma et al study 4.57% (total 394 patients), Binita Goswami et al study 46.1% (total 160 patients).^14,15,17,23 From the above data, estimation of both TSH and prolactin levels are important in infertility evaluation. The raised TRH secretion in primary hypothyroidism stimulates both TSH and prolactin secretion. In infertile females if hypothyroidism is associated with hyperprolactinemia, hypothyroidism should be treated first and TSH should be maintained at lower limit.

Significant association was noted between obesity and hyperprolactinemia. So all obese infertile females should have serum prolactin estimation. Serum prolactin and TSH levels showed significant positive correlation with body weight and BMI in secondary infertility. Obesity is associated with hormonal derangements which are responsible for infertility.²⁵ This is contrast to a recent study in general population where there was no correlation found between serum prolactin and obesity.²⁶ Conversely, another study comparing basal and TRH stimulated prolactin levels in obese and non-obese individuals showed higher basal levels of prolactin in obese individuals.²⁷ In overweight women with infertility, weight loss should be considered as a first line treatment.

To reduce BMI, to prevent obesity related metabolic changes and to improve fertility, life style modification should be advised.

In our study 24.6% of females were having abnormal menstrual cycles, this is contrast to other studies. In Avasti et al study 57.6%, in Muhammad et al study 90.2%, in Akhther et al study it was 70%, Salah et al study 66.7% (150 patients), in Goswami B et al study 61.2%.^8,15,16,18 Mild to moderate hyperprolactinemia does not correlate with either the degree or presence/absence of menstrual disturbances.²⁴ Prevalence of ovulatory dysfunction, as one of the causes of female infertility, has been variously reported in different studies.

CONCLUSION

24.67% of infertile women had raised prolactin levels and 25.6% of women were having hypothyroidism associated with hyperprolactinemia. In hypothyroid infertile women if associated with hyperprolactinemia, the first treatment should be to correct the hypothyroidism and maintain TSH at lower limit. Association between galactorrhea & obesity with hyperprolactinemia is significant, so serum prolactin estimation should be done in infertile females either with galactorrhea or obesity. Lifestyle modification should be advised to reduce BMI along with or prior to infertility treatment. Mild hyperprolactinemia can cause infertility even with regular menstruation. Hyperprolactinemia is one of the most common endocrinological disorders of female infertility and it is often associated with hypothyroidism. So all infertile women should be offered serum prolactin and Thyroid Stimulating Hormone (TSH) estimation at an early stage of infertility checkup rather than going for more costly tests or invasive procedures.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the institutional ethics committee

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