Kisspeptin

Introduction

Structure and Source

• Kisspeptin-1 (KISS1) is the parent peptide; it is cleaved into shorter bioactive fragments: kisspeptin-54, -14, -13, and -10 (the number denotes amino acid length).
• Kisspeptin-10 is the shortest biologically active form and contains the RF-amide motif essential for receptor binding.
• Produced by KNDy neurons (Kisspeptin, Neurokinin B, Dynorphin) in the arcuate nucleus of the hypothalamus.
• Also produced in the anteroventral periventricular nucleus (AVPV) - important for the LH surge.
• Additional production sites: placenta, gonads, liver, bone.

Mechanism of Action

• Neurokinin B (NKB) binds NK3R on adjacent KNDy neurons -> stimulates kisspeptin release (the "on" signal)
• Dynorphin (Dyn) acts on kappa-opioid receptors on KNDy neurons -> inhibits kisspeptin release (the "off" signal, terminating each pulse)
• This self-regulating loop creates the rhythmic, synchronized pulsatile release of GnRH

1. Kisspeptin binds GPR54 on GnRH neuron cell bodies AND on GnRH nerve terminals in the median eminence
2. GnRH is released in pulses into the hypothalamic-pituitary portal vasculature
3. GnRH stimulates pituitary gonadotropes -> pulsatile LH and FSH release
4. LH/FSH act on ovaries/testes -> sex steroid production

Feedback Regulation

Role in Puberty

• During childhood, GnRH secretion is suppressed by inhibitory GABAergic tone and other neuroendocrine brakes.
• At puberty onset: kisspeptin signaling increases, overcoming the inhibitory brake -> reactivation of GnRH pulses.
• Puberty initially shows nocturnal LH/FSH surges, then progresses to round-the-clock pulsatility.
• Leptin (from adipocytes) plays a permissive role, likely acting through kisspeptin neurons - explaining why severe undernutrition delays puberty.
• MKRN3 (Makorin ring finger protein 3) acts as an upstream inhibitor of kisspeptin; loss-of-function mutations in MKRN3 "remove the brake" and cause central precocious puberty.

Role in the Menstrual Cycle

1. Follicular phase: Low, pulsatile kisspeptin drives steady GnRH/FSH/LH pulses -> follicle development.
2. Pre-ovulatory LH surge: Rising estradiol switches from negative to positive feedback -> activates AVPV kisspeptin neurons -> massive LH surge -> triggers ovulation. Goodman & Gilman describes this as "an estrogen-induced rise in kisspeptin and a change in pituitary responsiveness to GnRH."
3. Luteal phase: Progesterone + estrogen suppress arcuate kisspeptin -> lower GnRH frequency.

Clinical Significance

1. Hypogonadotropic Hypogonadism (HH)

• Loss-of-function mutations in KISS1 gene or GPR54 (KISS1R) -> normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
• Patients fail to enter puberty; low LH, FSH, sex steroids; normal olfaction (unlike Kallmann syndrome).
• Mutations in NKB (TAC3) or its receptor (TACR3) also cause HH by disrupting kisspeptin stimulation.

2. Central Precocious Puberty (CPP)

• Gain-of-function (activating) mutations in KISS1 or KISS1R -> premature activation of HPG axis -> CPP.
• MKRN3 loss-of-function mutations are the most common genetic cause of CPP.
• DLK1 (Delta-like homolog 1) loss-of-function also associated with CPP.

3. Role in the LH Surge / Ovulation Trigger (IVF Context)

• Kisspeptin is being studied as an alternative LH surge trigger in IVF cycles.
• Exogenous kisspeptin-54 injection can reliably trigger oocyte maturation in women undergoing controlled ovarian stimulation.
• Advantage: unlike hCG trigger, kisspeptin may reduce the risk of ovarian hyperstimulation syndrome (OHSS) because it produces a more physiological, self-limiting LH surge.
• Phase II trials have shown good oocyte yield with kisspeptin trigger, particularly relevant for women at high risk of OHSS.

4. Kisspeptin in Pregnancy and Preeclampsia

• Placenta is a major source of kisspeptin during pregnancy; serum kisspeptin levels rise dramatically during the first trimester and peak in the third trimester.
• Kisspeptin suppresses GnRH/LH/FSH during pregnancy (explaining gonadal quiescence).
• Markedly elevated in preeclampsia compared to normal pregnancy - may reflect abnormal trophoblast function; proposed as a biomarker for preeclampsia.
• Low first-trimester kisspeptin levels are associated with poor placentation and adverse pregnancy outcomes.

5. Polycystic Ovary Syndrome (PCOS)

• Elevated kisspeptin activity may contribute to increased GnRH pulse frequency seen in PCOS, driving preferential LH over FSH secretion and androgen excess.

6. Hypothalamic Amenorrhea (Functional)

• Stress, excessive exercise, and low energy availability suppress kisspeptin neurons (via NPY/AgRP pathways and low leptin), leading to reduced GnRH pulsatility and amenorrhea.

Therapeutic Potential

Summary Box

• Harrison's Principles of Internal Medicine 22E (2025), Chapters 403 & 404
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Chapter 48
• Guyton & Hall Textbook of Medical Physiology - Chapter 82
• Goldman-Cecil Medicine, Chapter on Reproductive Endocrinology
• Koysombat K et al. "Kisspeptin and neurokinin B: roles in reproductive health." Physiol Rev 2025 - a recent comprehensive review confirming therapeutic potential (PMID: 39813600)

Fertility-Preserving Surgery in Obstetrics & Gynecology

Introduction

I. BENIGN CONDITIONS

1. Myomectomy (for Uterine Fibroids)

• Preserves the uterus and endometrial cavity.
• Adhesion formation post-myomectomy can impair future fertility; careful hemostasis and anti-adhesion measures are essential.
• Recurrence rate of fibroids is ~27% at 40 months by TVS; patients should be counseled.
• Uterine rupture in subsequent pregnancy is a recognized risk, especially after deep intramural myomectomy; cesarean section is usually recommended.

2. Ovarian Cystectomy (for Benign Ovarian Cysts / Endometrioma)

• Laparoscopic cystectomy (enucleation) is preferred over aspiration or fenestration.
• For endometriomas, cystectomy is preferred over drainage/coagulation as it reduces recurrence and is associated with better pain relief - but note it can reduce ovarian reserve (AMH may fall). This is a critical counseling point.
• Ovarian cortex damage during endometrioma cystectomy is the main risk to fertility.
• Avoid bilateral oophorectomy unless absolutely necessary; always aim to preserve ovarian cortex.

3. Surgery for Endometriosis

• Conservative surgery (laparoscopic excision/ablation of endometriotic lesions, adhesiolysis) improves spontaneous pregnancy rates.
• Colorectal endometriosis: A fertility-preserving operation (rather than bowel resection + BSO) provided symptom relief in 76% of women in one study; BSO provided 86% relief but at the cost of fertility and premature menopause.
• Target: remove all visible disease while preserving both ovaries and uterus.

4. Tubal Surgery (Salpingostomy / Tuboplasty)

• For ectopic pregnancy: Salpingostomy (linear incision + removal of ectopic) vs. salpingectomy. Salpingostomy is fertility-preserving but carries a ~15-20% risk of persistent ectopic trophoblast - requires serum beta-hCG follow-up.
• Preferred if the contralateral tube is damaged or absent.
• Tubal reanastomosis after sterilization: best results when >4 cm of tube remains and the procedure was performed with clips (reversible method).

5. Cervical Cerclage (for Cervical Incompetence)

• Preserves the pregnancy in women with cervical incompetence.
• McDonald's or Shirodkar's cerclage.
• Transabdominal cerclage for anatomically short cervix.

II. GYNECOLOGICAL MALIGNANCIES

1. Cervical Cancer

• Young woman wishing to preserve fertility
• FIGO Stage IA1 to IB1 (selected IB2)
• Squamous or adenocarcinoma
• Lesion size ≤2 cm
• No lymphovascular space invasion (LVSI) for the most conservative approach
• No lymph node metastases
• Adequate length of proximal cervix must remain (≥1 cm above lesion)

• Devised by Dargent (1994); the vaginal radical trachelectomy (VRT) is most widely practiced.
• A cervical cerclage is placed at the time of surgery to maintain uterine competence.
• Selection criteria (strict): lesion ≤2 cm, no nodal involvement, no LVSI, adequate proximal margin, patient understands risk.
• Pregnancy rates post-trachelectomy: ~50-70% achieve pregnancy; spontaneous abortion and preterm delivery rates are higher.
• After radical trachelectomy, all pregnancies require close surveillance; elective cesarean section at 36-37 weeks.

2. Endometrial Cancer / Atypical Endometrial Hyperplasia

• Histology: Grade 1 endometrioid adenocarcinoma OR atypical hyperplasia
• MRI staging: No myometrial invasion (or minimal superficial only)
• No extrauterine disease
• No contraindication to progestins
• Patient desires fertility and understands the risks
• Must consent to close follow-up with endometrial biopsies

• Megestrol acetate 40-160 mg/day OR Levonorgestrel-IUS (Mirena) - local delivery, fewer systemic side effects.
• Response rate: ~76% regression overall; median time to regression = 12 weeks.
• Recurrence rate: 24% among responders; most within 1 year.
• After achieving regression confirmed on biopsy, patient should attempt pregnancy promptly.
• Definitive hysterectomy + staging is recommended after completion of childbearing.
• Endometrial biopsy every 3-6 months during treatment to assess response.

3. Ovarian Tumors

• Unilateral salpingo-oophorectomy (USO) OR unilateral cystectomy is acceptable for Stage I disease.
• Though cystectomy carries higher recurrence risk than oophorectomy, overall survival is not compromised.
• Contralateral ovary and uterus are preserved.
• Close follow-up with ultrasound.

• Unilateral salpingo-oophorectomy + surgical staging (peritoneal washing, omentectomy, lymph node sampling).
• Contralateral ovary and uterus retained.
• Adjuvant BEP chemotherapy (bleomycin, etoposide, cisplatin) as needed.
• Excellent prognosis; pregnancy rates after treatment are good.

• Stage IA: USO + surgical staging.

• Selected cases may be managed with USO + staging.
• Highly controversial; must be thoroughly counseled.

4. Ovarian Transposition (Oophoropexy)

• Indication: Women requiring pelvic radiotherapy (e.g., for cervical cancer, Hodgkin's lymphoma) who wish to preserve ovarian function.
• The ovaries are surgically transposed (moved) out of the radiation field, typically to the paracolic gutters or behind the uterus.
• Clips are placed to mark the transposed ovaries on imaging.
• Success rate: ~50-70% in preserving ovarian function.
• Risk: ~10-15% risk of ovarian metastasis in cervical cancer; therefore, must screen histology first.
• Ovarian function may be preserved in majority of women, avoiding premature menopause.

III. OTHER FERTILITY PRESERVATION ADJUNCTS (Surgical Context)

Summary Table

• Berek & Novak's Gynecology - Chapters on Endometrial Cancer, Cervical Cancer, Ovarian Tumors, Reproductive Endocrinology
• Creasy & Resnik's Maternal-Fetal Medicine - Chapter on Cervical Carcinoma
• Sabiston Textbook of Surgery - Chapter on Gynecologic Malignancies
• Goldman-Cecil Medicine - Reproductive Oncology chapter