Mid-Luteal Serum Progesterone in Infertile Women With Hypothyroidism Compared With Euthyroid Women With Proven Fertility: An Exploratory Case-Control Study

Abstract

Importance Hypothyroidism is linked to female infertility, but its association with luteal-phase progesterone remains uncertain.

Objective To compare mid-luteal serum progesterone in infertile women with untreated hypothyroidism and euthyroid women with proven fertility.

Design, Setting, And Participants This exploratory case-control study enrolled 107 women aged 25 to 44 years with untreated hypothyroidism and primary (n = 59) or secondary (n = 48) infertility, along with 95 euthyroid controls with proven fertility, at Arif Memorial Hospital in Lahore, Pakistan. Twelve enrolled controls were excluded for ineligibility. Women using hormonal medications, including ovulation induction agents or progesterone, were not eligible. Blood was collected 7 days before the next menses.

Exposures Serum progesterone, assessed continuously and in study-defined categories (<10, 10-20, and >20 ng/mL).

Main Outcomes And Measures The outcome was case status. Groups were compared using Mann-Whitney U tests and Hodges-Lehmann (HL) location shifts. Firth penalized logistic regression estimated adjusted odds ratios (aORs) controlling for age and reproductive hormones.

Results Median (IQR) progesterone was 18.5 (15.3-24.8) ng/mL in cases and 10.0 (8.0-13.5) ng/mL in controls (HL shift, 8.0 ng/mL; 95% CI, 6.6-10.0 ng/mL; P < .001). Progesterone exceeded 20 ng/mL in 39 cases (36.4%) and 1 control (1.1%) (aOR vs 10-20 ng/mL, 25.4; 95% CI, 4.9-264.5). Estimates were similar after restricting age and modeling it flexibly. Among 83 age-matched pairs, the paired HL shift was 7.1 ng/mL (95% CI, 4.8-9.1 ng/mL). The association was nonlinear: values below 10 ng/mL were more common in controls than cases (41.1% vs 14.0%). Progesterone did not differ between overt and subclinical hypothyroidism.

Conclusions And Relevance Infertile women with untreated hypothyroidism had higher single mid-luteal progesterone concentrations than euthyroid women with proven fertility. Because the groups differed in both fertility and thyroid status, the observed difference cannot be attributed specifically to hypothyroidism. The findings are hypothesis-generating and do not establish pathological progesterone excess or diagnostic utility.