Delayed Menstruation After Discontinuing Progesterone and Testosterone
The delayed menstruation is most likely caused by residual suppression of the hypothalamic-pituitary-ovarian axis from recent testosterone discontinuation, which disrupts normal ovarian function and endometrial development. 1
Primary Mechanism: Testosterone Withdrawal Effect
Exogenous testosterone disrupts normal ovarian function and endometrial development, causing menstrual delays even after discontinuation. 1 The suppressive effects on the HPO axis do not immediately resolve when testosterone is stopped, and it may take several weeks to months for normal cyclicity to resume.
The patient's history of hyperparathyroidism adds complexity, as both estradiol and progesterone can stimulate PTH secretion from abnormal parathyroid tissue. 2 However, this is unlikely to be the primary driver of menstrual delay.
Stress factors, including recent medication discontinuation, can further disrupt the hypothalamic-pituitary-ovarian axis and delay ovulation/menstruation. 1
Tirzepatide Considerations
Tirzepatide itself does not directly cause menstrual irregularities, but it has documented interactions with oral hormonal contraceptives due to delayed gastric emptying, particularly after the first dose. 3 However, this patient is not taking oral contraceptives.
In patients with hyperparathyroidism and chronic thiazide use, tirzepatide has been associated with severe hypercalcemia, 4 though this would not directly cause menstrual delay. Monitor calcium levels given the patient's hyperparathyroidism history.
Tirzepatide may indirectly affect ovarian function through interactions with IGF-1 and metabolic pathways, though this mechanism is not well-established. 1
Sermorelin (GHRH Analogue) Impact
Growth hormone secretion interacts with IGF-1 and metabolic function, which could indirectly affect ovarian function, 1 though this is not a primary mechanism for menstrual disruption.
No direct evidence links sermorelin to menstrual irregularities in the absence of other hormonal disruptions.
Diagnostic Algorithm
First, exclude pregnancy immediately using urine or serum β-hCG, as this is the most common cause of menstrual irregularity in reproductive-age women. 1
Second, obtain hormonal evaluation:
- Measure LH, FSH, and estradiol levels to assess ovarian function recovery after testosterone discontinuation. 1
- Calculate LH/FSH ratio (>2 suggests PCOS, though less likely with this clinical picture). 5
- Check total testosterone to confirm clearance of exogenous testosterone. 5
Third, evaluate for complications:
- Check serum calcium given hyperparathyroidism history and tirzepatide use. 4
- Perform thyroid function tests (TSH, free T4), as thyroid dysfunction elevates SHBG and causes menstrual irregularities. 5
- Consider pelvic ultrasound if hormonal tests suggest ovarian pathology. 5
Management Strategy
Discontinue or significantly reduce any remaining testosterone exposure to allow endogenous estrogen to rebuild the endometrium. 1 If testosterone was fully discontinued, allow 4-8 weeks for HPO axis recovery.
For symptomatic management of irregular bleeding if it occurs:
- First-line: NSAIDs such as mefenamic acid 500 mg three times daily for 5 days OR celecoxib 200 mg daily for 5 days during bleeding episodes. 5, 6
- Second-line: Low-dose combined oral contraceptives for 10-20 days if medically eligible and no contraindications (though avoid if bone health concerns exist). 5, 1
Consider progesterone withdrawal to induce menses once adequate endometrial development has occurred (typically 4-6 weeks after testosterone discontinuation). 1
Critical Pitfalls to Avoid
Do not assume a 10-day delayed period is "normal variation"—evaluate cycles >35 days apart as abnormal. 1
Do not continue testosterone at any dose without investigating its impact on menstrual function. 1
Do not overlook calcium monitoring in this patient with hyperparathyroidism taking tirzepatide, as severe hypercalcemia can occur, particularly with concurrent thiazide use. 4 Check baseline and follow-up serum calcium within 1-2 weeks.
Rule out pregnancy, thyroid dysfunction, and structural pathology before attributing menstrual delay solely to testosterone withdrawal. 5, 1
Referral Indications
Refer to endocrinology if:
- Hormonal workup reveals complex endocrine abnormalities. 5
- Calcium levels are elevated or PTH levels are abnormal. 4
- Menstrual cycles do not resume within 3 months of testosterone discontinuation.
Refer to gynecology if: