Role of hypothyroidism and associated pathways in pregnancy and infertility: Clinical insights.

PRL-secreting adenomas can also be a cause of hyperprolactinemia which can lead to infertility. This condition is generally treated with dopamine receptor agonist cabergoline and bromocriptine to restore fertility [ 60 ]. Elevated PRL due to any reason can cause HH and infertility. Hyperprolactinemia leads to direct suppression on GnRH neurons to suppress GnRH release [ 61 ]. Elevated PRL levels in hyperprolactinemia through inhibitory action reduce the levels of LH and FSH by inhibiting GnRH neurons in hypothalamus [ 62 ]. In recent years, a neuropeptide called kisspeptin, encoded by Kiss1 gene, a potent stimulus for GnRH secretion, has been recognized, having important value in pubertal maturation and regulation of reproductive function [ 63 ]. In a study, hyperprolactinemic mice were administered with intraperitoneal injections of kisspeptin once daily for 20 days. Interestingly, the results showed restoration of estrous cyclicity and increased LH and FSH levels. These results can implicate that the treatment with kisspeptin can benefit the fertility induction among hyperprolactinemic infertile patients [ 64 ]. Endometriosis is also seen as a risk factor for infertility. There is an anatomical basis for infertility in women with severe endometriosis, whereas in patients with mild endometriosis, the infertility cause is not been clearly defined [ 65 ]. According to some studies, the endometriosis-related infertility can be due to fluctuations in PRL secretion [ 66 ]. In contrast, some authors demonstrated normal basal PRL levels in the patients presented with endometriosis-associated infertility; however, these levels were altered after a TRH stimulation test, indicating an association between infertility in endometriosis patients and altered secretion patterns [ 67 ]. Infertile women with normal PRL levels when exposed to TRH stimulation test or metoclopramide (dopaminergic antagonist) have shown abnormal PRL secretion with exaggerated response to the interventions [ 68 ]. A case–control study to analyze the relation between endometriosis and altered PRL and growth hormone levels by Cunha-Filho et al . showed higher levels of PRL in infertile endometriosis women after TRH administration when compared to fertile patients without endometriosis. PRL levels showed no difference between the groups after the dopaminergic blockage. These results suggest relation between PRL secretion alterations in endometriosis patients and excluded the involvement of dopaminergic system [ 69 ]. The correlation between hypothyroidism and PRL in inducing infertility is summarized in Table 1 . Role of hypothyroidism and prolactin in infertility TSH: Thyroid-stimulating hormone

Assessment of thyroid hormones and the levels of serum PRL has been considered an important component in women with infertility [ 46 ]. The levels of TRH secretion is increased by hypothalamus due to feedback mechanism in hypothyroidism condition. The increased TRH affects the PRL and TSH levels by increasing their secretion by pituitary [ 47 ]. The increased TRH in hypothyroidism causes rise in PRL levels, and subsequently, the patients may have galactorrhea [ 48 ]. Impairment of pulsatile secretion of GnRH and interference with ovulation are the reasons that affect fertility associated with hyperprolactinemia [ 49 ]. A study conducted by Binita et al ., in 160 primary infertile women, showed a positive relation between serum levels of TSH and PRL among infertile women. Among the total study participants, 60% of infertile women showed menstrual disorders and 41% hyperprolactinemia. The infertile women with hypothyroidism have showed significant high levels of PRL when compared to euthyroid patients [ 50 ]. According to a study conducted by Bahar et al ., in 481 participants with subclinical hypothyroidism, the hyperprolactinemia prevalence was found to be 20.4% [ 51 ]. In a cross-sectional study on 200 infertile women, the levels of TSH values and PRL with infertility status was compared. Abnormal TSH and PRL levels were found to be 36 and 79, respectively, in infertile women, with none in fertile women. This shows a significant relation between hyperprolactinemia, hypothyroidism, and infertility [ 52 ]. In a study conducted by Snyder et al ., the hypothyroid patients were given thyroid-releasing hormone (TRH) 400 μg, T3 and T4. To the well-known fact that TRH has been shown to be a potent stimulus of PRL release, the results showed that TRH directly stimulated PRL secretion, whereas T3 and T4 inhibits it. Change in PRL response to TRH is associated with changes in normal T3 and T4 levels. TRH-induced PRL release is increased by subnormal serum T3 and T4 levels [ 53 ]. There is a high crude prevalence of hypothyroid-associated hyperprolactinemia in infertility. This stresses the fact that all infertility cases should be subjected for the estimation of serum PRL. The results of a study by Sharma et al . among patients with subclinical hypothyroidism (ScH) and primary hypothyroidism showed a positive correlation between TSH and PRL. A high specificity of >90% in detecting hyperprolactinemia is seen in female patients with TSH ≥7.51 mIU/L. The prevalence of hyperprolactinemia is higher in primary hypothyroidism compared to ScH [ 54 ]. A case of hyperprolactinemia due to ScH was treated by thyroid hormone replacement with levothyroxine; the patient's TSH levels and serum PRL levels returned to normal, indicating importance of thyroid hormone replacement therapy in managing hyperprolactinemia [ 55 ]. Changes in pituitary structure and pituitary endocrine cell hyperplasia are seen secondary to primary hypothyroidism [ 56 ]. Low levels of thyroid hormones lead to overproduction of TRH, followed by hypertrophy and hyperplasia of thyrotrophic cells and pituitary gland [ 57 ]. Thyroid hormone T3 was found to reduce PRL mRNA levels in pituitary; therefore, hypothyroidism leads to synthesis of more PRL. In primary hypothyroidism, reduced sensitivity to dopamine inhibitory effect on receptors is seen in pituitary [ 58 ]. Clearance of PRL from circulation is reduced in hypothyroidism [ 59 ].

Thyroid disorders were found to be the most common endocrine problems seen in the world. Among various thyroid disorders, the prevalence of hypothyroidism is more with about 4%–5% worldwide. Females are at more risk of developing hypothyroidism than males [ 1 ]. In pregnancy, thyroid pathology worsens with a frequency of 6-fold, so pregnancy is seen as a risk factor for thyroid disorders. Hypothyroidism in pregnancy can lead to increased risk of premature delivery, abortions, and intrauterine fetal deaths, which are associated with maternal morbidity [ 2 ]. During pregnancy, there will be a great physiological stress on mother and fetus. Physiology of thyroid is modified during pregnancy, which helps prepare the maternal thyroid gland to cope with metabolic demands. Some studies show that hypothyroid women have a decreased fertility rate than normal women, and even if they conceive, the children born will have a significant impairment of IQ levels, learning abilities, and neuropsychological issues [ 3 ]. There are several meta-analysis studies and randomized trials, confirming that subclinical hypothyroidism and thyroid autoimmunity are strongly associated with preterm deliveries and miscarriages during pregnancy and suggesting that treatment with levothyroxine may reduce the risks [ 4 5 ]. Pregnancy is affected by thyrotoxicosis at various stages and the conditions named accordingly as gestational thyrotoxicosis, new onset of Graves' disease during pregnancy, postpartum Graves' thyrotoxicosis (PPGD), and postpartum destructive thyrotoxicosis (PPT), with the highest prevalence of PPGD followed by PPT [ 6 ].

Thyroid disease requires special care in pregnant women or those desiring pregnancy. Untreated hypothyroidism during pregnancy can lead to infertility/subfertility, fetal deaths, premature deliveries, and abortions. Assessment of serum thyroid profile and PRL levels should be done in women desiring pregnancy and at early stage of infertility. Early intervention with appropriate therapy can avoid the fetal complications in pregnancy due to hypothyroidism and to improve fertility rate among infertile women. The tests for hyperprolactinemia and thyroid disorders should be made routine in pregnant and infertile women. Nil. There are no conflicts of interest.